Furopyridines as inhibitors of protein kinases

ABSTRACT

The invention relates to furo[3,2-b]pyridines substituted at least in position 5 as inhibitors of protein kinases, regulators or modulators, methods of preparation thereof, pharmaceutical compositions containing the compounds, and pharmaceutical use of the compounds and compositions in the treatment of the diseases such as, for example, cancer or neurodegenerative diseases.

FIELD OF THE INVENTION

The present invention relates to substituted furo[3,2-b]pyridines asinhibitors of various protein kinases, regulators or modulators,pharmaceutical compositions containing the compounds, and pharmaceuticaluse of the compounds and compositions in the treatment of the diseasessuch as, for example, cancer, inflammation, pain, neurodegenerativediseases or viral infections.

BACKGROUND ART

Protein kinases are involved in regulation of practically all processesthat are central to the growth, development, and homeostasis ofeukaryotic cells. In addition, some protein kinases have an importantrole in oncogenesis and tumor progression and several kinase inhibitorsare now approved for the treatment of cancer (D. J. Matthews and M. E.Gerritsen: Targeting protein kinases for cancer therapy, Wiley, 2010).

Examples of kinase inhibitors that are used in modern oncology include:imatinib (treatment of CML); dasatinib (CML with resistance to priortreatment, including imatinib); nilotinib (CML); bosutinib (CML);gefitinib (non-small cell lung cancer); erlotinib (non-small cell lungcancer and pancreatic cancer); lapatinib (breast cancer); sorafenib(metastatic renal cell carcinoma, hepatocellular cancer); vandetanib(metastatic medullary thyroid cancer); vemurafenib (inoperable ormetastatic melanoma); crizotinib (non-small cell lung cancer); sunitinib(metastatic renal cell carcinoma, gastrointestinal stromal tumor that isnot responding to imatinib, or pancreatic neuroendocrine tumors);pazopanib (renal cell carcinoma and advanced soft tissue sarcoma);regorafenib (metastatic colorectal cancer); cabozantinib (metastaticmedullary thyroid cancer); dabrafenib (BRAF V600E mutation-positiveadvanced melanoma); and trametinib (in combination with dabrafenib forthe treatment of BRAF V600E/K-mutant metastatic melanoma).

Various kinases are regarded as good targets for pharmacologicalinhibition in order to treat proliferative and/or neurodegenerativediseases. Biological and potential therapeutic significance of someselected kinases is briefly summarized below.

The regulation of splice site usage provides a versatile mechanism forcontrolling gene expression and for the generation of proteomediversity, playing an essential role in many biological processes. Theimportance of alternative splicing is further illustrated by theincreasing number of human diseases that have been attributed tomis-splicing events. Appropriate spatial and temporal generation ofsplicing variants demands that alternative splicing be subjected toextensive regulation, similar to transcriptional control. The CLK(Cdc2-like kinase) family has been implicated in splicing control(Experimental Cell Research 1998, 241, 300.). Pharmacological inhibitionof CLK1/Sty results in blockage of SF2/ASF-dependent splicing ofbeta-globin pre-mRNA in vitro by suppression of CLK-mediatedphosphorylation. It also suppresses dissociation of nuclear speckles aswell as CLK1/Sty-dependent alternative splicing in mammalian cells andwas shown to rescue the embryonic defects induced by excessive CLKactivity in Xenopus (Journal of Biological Chemistry 2004, 279, 24246.).

Alternative mRNA splicing is a mechanism to regulate protein isoformexpression and is regulated by alternative splicing factors. Thealternative splicing factor 45 (SPF45) is overexpressed in cancer andits overexpression enhances two processes that are important formetastasis, i.e. cell migration and invasion, dependent on biochemicalregulation by CLK1 (Nucleic Acids Research 2013, 41, 4949.). CLK1phosphorylates SPF45 on eight serine residues. CLK1 expression enhances,whereas CLK1 inhibition reduces, SPF45-induced exon 6 exclusion from FasmRNA. Inhibition of CLK1 increases SPF45 degradation through aproteasome-dependent pathway. In addition, small-molecule inhibitors ofspecific CLKs can suppress HIV-1 gene expression and replication(Retrovirology 2011, 8, 47.), which could be used in concert withcurrent drug combinations to achieve more efficient treatment of theinfection. Inhibition of CLK1 can be applicable in the treatment ofAlzmeimer's disease (Current Drug Targets 2014, 15, 539.).

DYRK (dual specificity tyrosine phosphorylation-regulated kinase) familyenzymes are essential components of important signaling cascades in thepathophysiology of cancer and Alzheimer's disease and their biologicalexpression levels regulate key signaling processes in these diseases. Inparticular, DYRK2 is over-expressed in adenocarcinomas of the esophagusand lung (Cancer Research 2003, 63, 4136.) and DYRK1A in glioblastomawhere its inhibition compromised tumors'survival and produced a profounddecrease in tumor burden (Journal of Clinical Investigation 2013, 123,2475.). DYRK1B activation that is induced by microtubule damage triggersmicrotubule stabilization and promotes the mitochondrial translocationof p21Cip1/waf1 to suppress apoptosis. Its inhibition caused reducedviability of cancer cells (ACS Chemical Biology 2014, 9, 731.).Correspondingly, it has been understood that inhibition of DYRK kinasesalone or in combination with other chemotherapeutic drugs may have tumorsuppression effect and the enzymes are therefore appropriate targets forpharmacological inhibition (Bioorgank & Medicinal Chemistry Letters2013, 23, 6610; Medicinal Chemistry Research 2014, 23, 1925.).

In addition, DYRK kinases are also over-expressed in neurodegenerativediseases such as Alzheimer's disease, Parkinson's disease, Huntington'sdisease, and Pick disease (Neurobiology of Disease 2005, 20, 392;Cellular and Molecular Life Sciences 2009, 66, 3235.).

HIPK2 (homeodomain-interacting protein kinase) is a tumor suppressor andfunctions as an evolutionary conserved regulator of signaling and geneexpression. This kinase regulates a vast array of biological processesthat range from the DNA damage response and apoptosis to hypoxiasignaling and cell proliferation. Recent studies showed the tightcontrol of HIPK2 by hierarchically occurring posttranslationalmodifications such as phosphorylation, small ubiquitin-like modifiermodification, acetylation, and ubiquitination. Dysregulation of HIPK2can result in increased proliferation of cell populations as it occursin cancer or fibrosis. Inappropriate expression, modification, orlocalization of HIPK2 can be a driver for these proliferative diseases(Journal of Molecular Medicine 2013, 91, 1051.).

FMS-like tyrosine kinase 3 (FLT3), a receptor tyrosine kinase (RTK), isa membrane-bound receptor with an intrinsic tyrosine kinase domain. Itsactivation regulates a number of cellular processes (e.g. phospholipidmetabolism, transcription, proliferation, and apoptosis), and throughthese processes, FLT3 activation plays a critical role in governingnormal hematopoiesis and cellular growth Expression of FLT3 has beenevaluated in hematologic malignancies. The majority of B-cell acutelymphocytic leukemia (ALL) and acute myeloid leukemia (AML) blasts(>90%) express FLT3 at various levels (Clinical Cancer Research 2009,15, 4263.). Overexpression or/and activating mutation of FLT3 kinaseplay a major driving role in the pathogenesis of acute myeloid leukemia(AML). Hence, pharmacologic inhibitors of FLT3 are of therapeuticpotential for AML treatment (Oncologist 2011, 16, 1162; PLoS One 2014,9, e83160/1; Leukemia Lymphoma 2014, 55, 243.).

Tropomyosin-related kinase (TRK) is a family of three RTKs (TRK-A,TRK-B, TRK-C) regulating several signaling pathways that are importantfor survival and differentiation of neurons. TRK-A regulatesproliferation and is important for development and maturation of thenervous system, promotes survival of cells from death. Point mutations,deletions and chromosomal rearrangements cause ligand-independentreceptor dimerization and activation of TRK-A. In mutated version ofTRK, abnormal function will render cells unable to undergodifferentiation in response to ligand in their microenvironment, so theywould continue to grow when they should differentiate, and survive whenthey should die. Activated TRK-A oncogenes have been associated withseveral human malignancies, e.g., breast, colon, prostate, thyroidcarcinomas and AML (Cell Cycle 2005, 4, 8; Cancer Letters 2006, 232,90.). In addition, inhibition of TRK can be relevant for the treatmentof inflammation (PLoS One 2013, 8, e83380.) and pain (Expert Opinion onTherapeutic Patients 2009, 19, 305.).

In summary, there is a need for inhibitors of different protein kinasesin order to treat or prevent disease states associated with abnormalregulation of the kinases-mediated biological processes.

DISCLOSURE OF THE INVENTION

The present invention provides substituted furo[3,2-b]pyridinecompounds, methods of preparing such compounds, pharmaceuticalcompositions comprising one or more of such compounds, and their use inthe treatment, prevention, inhibition or amelioration of one or morediseases associated with protein kinases using such compounds orpharmaceutical compositions.

The present invention provides compounds represented by the structuralformula (I):

or a pharmaceutically acceptable salt, solvate or a prodrug thereof,wherein:

L⁵ is selected from the group consisting of a bond, —N(R¹¹)—;

L² is selected from the group consisting of a bond, —O—;

L³ is selected from the group consisting of a bond, —N(R¹¹)—, —O—;

L⁶ is selected from the group consisting of a bond, —O—;

L⁷ is selected from the group consisting of a bond, —N(R¹¹)—;

R⁵ is selected from the group consisting of C₁-C₆ alkyl; aryl;heteroaryl; biaryl; bi(heteroaryl); cycloalkylaryl; heterocyclylaryl;heteroarylaryl; arylheteroaryl; cycloalkylheteroaryl;heterocyclylheteroaryl; wherein each of the substituent moieties can beunsubstituted or optionally substituted;

R² is selected from the group consisting of H; —CF₃; NH₂; —Cl; —Br; —F;C₁-C₆ alkyl;

R³ is selected from the group consisting of H; C₁-C₆ alkyl; aryl;cycloalkyl; heteroaryl; biaryl; heteroarylaryl; arylheteroaryl; whereineach of the substituent moieties can be unsubstituted or optionallysubstituted;

R⁶ is selected from the group consisting of H; —CF₃; NH₂; —Cl; —Br; —F;C₁-C₆ alkyl; aryl; heteroaryl; wherein each of the substituent moietiescan be unsubstituted or optionally substituted;

R⁷ is selected from the group consisting of H; C₁-C₆ alkyl; aryl;cycloalkyl; heteroaryl; biaryl; heteroarylaryl; arylheteroaryl; whereineach of the substituent moieties can be unsubstituted or optionallysubstituted;

R¹¹ is selected from the group consisting of H, C₁-C₆ alkyl;

provided that the substituent in position 5 (L5-R5) is not oxadiazolylor methyl-oxadiazolyl.

As used in this disclosure, the following terms, unless otherwiseindicated, have the following meanings:

“alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and contains 1 to 6 carbon atoms, more preferably 1 to 4 carbonatoms in the chain. Examples of suitable alkyls are methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl,hexyl. The alkyl can be unsubstituted or optionally substituted by oneor more substituents which can be the same or different, eachsubstituent being independently selected from the group consisting of F,Cl, Br, CF₃, OCF₃, OR⁹, SR⁹, SOH, SO₂H, SO₂N(H, C₁-C₄ alkyl)₂, CHO,COO(H, C₁-C₄ alkyl), COH, C(O)N(H, C₁-C₄ alkyl), O(CH₂)_(p)N(CH₃)₂ andNR⁹R¹⁰;

“aryl” means an aromatic monocyclic or polycyclic ring system containing6 to 14 carbon atoms, preferably 6 to 10 carbon atoms. Examples ofsuitable aryls are phenyl, naphthyl. The aryl can be unsubstituted oroptionally substituted by one or more substituents which can be the sameor different, each substituent being independently selected from thegroup consisting of F, Cl, Br, CF₃, OCF₃, OR⁹, SR⁹, SOH, SO₂H, SO₂N(H,C₁-C₄ alkyl)₂, CHO, COO(H, C₁-C₄ alkyl), COH, C(O)N(H, C₁-C₄ alkyl),NR⁹R¹⁰, —(CR⁹R¹⁰)_(p)R^(9a), O(CH₂)_(p)N(CH₃)₂ and —(CR⁹R¹⁰)_(p)OR^(9a);

“cycloalkyl” means an aliphatic monocyclic or bicyclic ring systemcomprising 3 to 10 carbon atoms, preferably 5 to 7 carbon atoms.Suitable examples include cyclopentyl, cyclohexyl, cycloheptyl,1-decalinyl, norbornyl, adamantyl. The cycloalkyl can be unsubstitutedor optionally substituted by one or more substituents which can be thesame or different, each substituent being independently selected fromthe group consisting of F, Cl, Br, CF₃, OCF₃, OR⁹, SR⁹, SOH, SO₂H,SO₂N(H, C₁-C₄ alkyl)₂, CHO, COO(H, C₁-C₄ alkyl), COH, C(O)N(H, C₁-C₄alkyl), NR⁹R¹⁰), —(CR⁹R¹⁰)_(p)R^(9a), O(CH₂)_(p)N(CH₃)₂ and—(CR⁹R¹⁰)_(p)OR^(9a);

“heterocyclyl” means an aliphatic monocyclic or bicyclic ring systemcontaining 3 to 10 carbon atoms, preferably 4 to 8 carbon atoms, and atleast one heteroatom selected from the group consisting of nitrogen,oxygen and sulfur. Suitable examples include piperazinyl andmorpholinyl. Preferably, heterocyclyl is not a bicyclic ring systemcontaining only N heteroatoms. The heterocyclyl can be unsubstituted oroptionally substituted by one or more substituents which can be the sameor different, each substituent being independently selected from thegroup consisting of F, Cl, Br, CF₃, OCF₃, OR⁹, SR⁹, SOH, SO₂H, SO₂N(H,C₁-C₄ alkyl)₂, CHO, COO(H, C₁-C₄ alkyl), COH, C(O)N(H, C₁-C₄ alkyl),NR⁹R¹⁰), —(CR⁹R¹⁰)_(p)R^(9a), O(CH₂)_(p)N(CH₃)₂ and—(CR⁹R¹⁰)_(p)OR^(9a);

“heteroaryl” means an aromatic monocyclic or bicyclic ring systemcontaining 1 to 14 carbon atoms, preferably 3 to 7 carbon atoms, mostpreferably 3 to 5 carbon atoms, and at least one heteroatom selectedfrom the group consisting of nitrogen, oxygen and sulfur. Examples ofsuitable heteroaryls are pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl,furanyl, thienyl, oxazolyl, thiazolyl, isothiazolyl, isoxazolyl,pyrrolyl, imidazolyl. Preferably, heteroaryl is not indolyl, indolinolylor imidazopyridazinyl. The heteroaryl can be unsubstituted or optionallysubstituted by one or more substituents which can be the same ordifferent, each substituent being independently selected from the groupconsisting of F, Cl, Br, CF₃, OCF₃, OR⁹, SR⁹, SOH, SO₂H, SO₂N(H, C₁-C₄alkyl)₂, CHO, COO(H, C₁-C₄ alkyl), COH, C(O)N(H, C₁-C₄ alkyl), NR⁹R¹⁰,—(CR⁹R¹⁰)_(p)R^(9a), O(CH₂)_(p)N(CH₃)₂ and —(CR⁹R¹⁰)_(p)OR^(9a);

“biaryl” means an aryl-aryl- group in which each of the aryls isindependently as previously described. An example is biphenyl;

“bi(heteroaryl)” means an heteroaryl-heteroaryl- group in which each ofthe heteroaryls is independently as previously described;

“cycloalkylaryl” means a cycloalkyl-aryl- group in which the cycloalkyland aryl are as previously described;

“heterocyclylaryl” means a heterocyclyl-aryl- group in which theheterocyclyl and aryl are as previously described;

“heteroarylaryl” means a heteroaryl-aryl- group in which the heteroaryland aryl are as previously described;

“arylheteroaryl” means a aryl-heteroaryl- group in which the aryl andheteroaryl are as previously described;

“cycloalkylheteroaryl” means a cycloalkyl-heteroaryl- group in which theheteroaryl and cycloalkyl are as previously described;

“heterocyclylheteroaryl” means a heterocyclyl-heteroaryl- group in whichthe heterocyclyl and heteroaryl are as previously described;

wherein

each of aryl, cycloalkyl, heterocyclyl, heteroaryl, biaryl,bi(heteroaryl), cycloalkylaryl, heterocyclylaryl, heteroarylaryl,arylheteroaryl, cycloalkylheteroaryl, and heterocyclylheteroaryl can bebound directly or via a methylene or ethylene spacer;

p is an integer in the range of from 1 to 7, more preferably from 1 to5, even more preferably 1 to 3;

R⁹ is H or C1-C6 alkyl, unsubstituted or optionally substituted by —OH,—NH₂, —N(CH₃)₂;

R^(9a) is H or C1-C6 alkyl, unsubstituted or optionally substituted by—OH, —NH₂, —N(CH₃)₂;

R¹⁰ is H or C1-C6 alkyl, unsubstituted or optionally substituted by —OH,—NH₂, —N(CH₃)₂.

In a preferred embodiment, R⁵ is selected from the group consisting ofaryl; heteroaryl; heterocyclylaryl; heteroarylaryl; arylheteroaryl;heterocyclylheteroaryl; wherein each of the substituent moieties can beunsubstituted or optionally substituted, preferably by at least onesubstituent selected from the group consisting of F, Cl, Br, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy,propoxy, isopropoxy, OH, NH₂, N(CH₃)₂, O(CH₂)_(p)N(CH₃)₂. Morepreferably, R⁵ is selected from the group consisting of aryl;heteroaryl; wherein each of the substituent moieties can beunsubstituted or optionally substituted, preferably by at least onesubstituent selected from the group consisting of F, Cl, Br, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy,propoxy, isopropoxy, OH, NH₂, N(CH₃)₂, O(CH₂)_(p)N(CH₃)₂. Even morepreferably, the heteroaryl in R⁵ is pyrazolyl.

In a preferred embodiment, any of L⁵, L⁷ is independently selected fromthe group consisting of a bond, —NH—.

In another preferred embodiment, any of L², L⁶ is a bond.

In yet another preferred embodiment, L³ is a bond or —O—.

In a preferred embodiment, R³ is selected from the group consisting ofaryl; heteroaryl; biaryl; wherein each of the substituent moieties canbe unsubstituted or optionally substituted, preferably by at least onesubstituent selected from the group consisting of F, Cl, Br, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy,propoxy, isopropoxy, OH, NH₂, N(CH₃)₂, O(CH₂)_(p)N(CH₃)₂. Even morepreferably, the aryl in R³ is phenyl, naphthyl (e.g., 2-naphthyl) andthe biaryl in R³ is biphenyl (e.g., 3-biphenyl).

In a preferred embodiment, R⁶ is selected from the group consisting ofH; —Cl; —Br; —F; —OH; —NH₂; or methyl.

In a preferred embodiment, R² is selected from the group consisting ofH; —Cl; —Br; —F; OH; —NH₂; or methyl.

In a preferred embodiment, R⁷ is selected from the group consisting ofH; C₁-C₆ alkyl; aryl; heteroaryl; wherein each of the substituentmoieties can be unsubstituted or optionally substituted, preferably byat least one substituent selected from the group consisting of F, Cl,Br, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,methoxy, ethoxy, propoxy, isopropoxy, OH, NH₂, N(CH₃)₂,O(CH₂)_(p)N(CH₃)₂.

Preferably, at least one of R³ and R⁷ is not H when the corresponding L(i.e., L³ or L⁷, respectively) is a bond.

In a preferred embodiment, -L²-R², -L⁶-R⁶, -L⁷-R⁷ are hydrogens and -L³,—R³ is not hydrogen.

In one preferred embodiment, -L²-R², -L⁶-R⁶, -L⁷-R⁷ are hydrogens,-L³-R³ is aryl or biaryl (optionally substituted) and -L⁵-R⁵ isheteroaryl (optionally substituted).

In a preferred embodiment, any of aryl; cycloalkyl; heterocyclyl;heteroaryl; biaryl; bi(heteroaryl); cycloalkylaryl; heterocyclylaryl;heteroarylaryl; arylheteroaryl; cycloalkylheteroaryl;heterocyclylheteroaryl is unsubstituted or substituted with at least onesubstituent selected from the group consisting of NH₂, N(CH₃)₂, OH,methoxy, ethoxy, propoxy, isopropoxy, methyl, ethyl, propyl, isopropyl,butyl, isobutyl and tert-butyl.

In another preferred embodiment, any of -L²-R², -L³-R³, -L⁶-R⁶, -L⁷-R⁷,-L⁵-R⁵ can be hydroxy(C₁-C₆)alkylamino, amino(C₁-C₆)alkylamino ordimethylamino(C₁-C₆)alkylamino.

Pharmaceutically acceptable salts are salts with acids or bases, or acidaddition salts. The acids and bases can be inorganic or organic acidsand bases commonly used in the art of formulation, such ashydrochloride, hydrobromide, sulfate, bisulfate, phosphate, hydrogenphosphate, acetate, benzoate, succinate, fumarate, maleate, lactate,citrate, tartarate, gluconate, methanesulfonate, benzenesulfonate,para-toluenesulfonate, primary, secondary and tertiary amides, ammonia.

In general, the compounds described in this invention can be preparedthrough the general routes described below in Schemes 1-6.

Pd-catalyzed coupling of 6-chloro-2-iodopyridin-3-ol with vinylboronates provides intermediate 1 (as shown in Scheme 1), whosecopper-mediated closure provides the furopyridine system in intermediate2. Subsequent Pd-catalyzed coupling of intermediate 2 with properC-nucleophiles leads to compounds 3 with R⁵ substituent attached via C—Cbond.

Alternatively, intermediate 2 can be subjected to amination to yieldamine-containing compounds 4 depicted in Scheme 2.

Also, 5-chlorofuro[3,2-b]pyridine can be converted into iodide 5, whichcan be brominated to yield intermediate 6 (Scheme 3). Sequentialchemoselective Pd-catalyzed couplings provide target compounds 3 whereR⁵ and R³ are different aryls or heteroaryls (Scheme 3).

Reaction of 6-chloro-2-iodopyridin-3-ol with trimethylsilylacetylenegives the furopyridine intermediate 8, which can be subjected to aPd-catalyzed coupling (e.g. Suzuki reaction) and subsequent N-oxidationfollowed by the treatment with POCl₃ to yield chlorinated intermediate10, as illustrated in Scheme 4.

The TMS group in 10 can be removed by KF in methanol to yieldintermediate 11, which can be subjected to Pd-catalyzed C—C bondformation or amination (indicated in Scheme 5) to yield compounds 12 and13, respectively.

As depicted in Scheme 6, 6-chloro-2-iodopyridin-3-ol can be allylated togive intermediate 14, which can be cyclized to furopyridine intermediate15, which upon Pd-catalyzed C—C bond formation or amination yieldscompounds 16 and 17, respectively.

Compounds 16 can be further elaborated (shown in Scheme 7) byN-oxidation-chlorination sequence to yield chlorinated intermediate 18,which can be subjected to Pd-catalyzed C—C bond formation or aminationto yield compounds 19 and 20, respectively.

In addition, iodination of 5-bromopyridin-3-ol provides intermediate 21,which can be converted into compound 22. Subsequent Pd-catalyzedcoupling followed by N-oxidation and regioselective chlorination yieldchloride 24 (Scheme 8).

Another Pd-catalyzed coupling on intermediate 24, followed by the byN-oxidation-chlorination sequence and another Pd-catalyzed couplingprovide intermediate 26. Removal of the TMS group, followed by finalPd-catalyzed coupling provide target compounds 27 with substituents atpositions 7- and 5, respectively (Scheme 9).

The compounds of formula (I) can be useful as protein kinase inhibitorsand can be useful in the treatment and prevention of proliferativediseases, e.g. cancer, inflammation and arthritis, neurodegenerativediseases such as Alzheimer's disease, cardiovascular diseases, viraldiseases, and fungal diseases. In one preferred embodiment, the proteinkinase is not GSK3. In another preferred embodiment, the protein kinaseis selected from CLK2, CLK4, HIPK1, HIPK2, HIPK3, FLT3, TRKA and DYRK2.

The present invention thus provides the compounds of formula (I) for useas medicaments. More specifically, it provides the compounds of formula(I) for use in the treatment and prevention of conditions selected fromproliferative diseases, neurodegenerative diseases, cardiovasculardiseases, pain, viral diseases, and fungal diseases.

The present invention also provides a method for treatment, inhibition,amelioration or prevention of a condition selected from proliferativediseases, neurodegenerative diseases, cardiovascular diseases, pain,viral diseases, and fungal diseases, in a patient suffering from suchcondition, comprising the step of administering at least one compound offormula (I) to said patient.

The present invention further includes pharmaceutical compositionscomprising at least one compound of formula (I) and at least onepharmaceutically acceptable auxiliary compound. The auxiliary compoundsmay include, e.g., carriers, diluents, fillers, preservatives,stabilisers, binders, wetting agents, emulsifiers, buffers, etc.Suitable auxiliary compounds are well known to those skilled in the artof formulation. The pharmaceutical compositions are prepared by knownmethods, e.g., mixing, dissolving etc.

EXAMPLES OF CARRYING OUT THE INVENTION Preparative Example 1

To a solution of (PhO)₃P (2.09 g; 6.75 mmol) in anhydrous CH₂Cl₂ (10 mL)was added Br₂ (0.380 mL; 7.38 mmol) dropwise under Ar atmosphere at −60°C. Then triethylamine (1.10 mL; 7.89 mmol) and a solution of2-acetonaphthone (1.03 g; 6.05 mmol) in anhydrous CH₂Cl₂ (5 mL) wereadded. The resulting reaction mixture was stirred under Ar for 18 h,while warming to 25° C., and then heated to reflux for additional 2 h.Then, the CH₂Cl₂ and excess of triethylamine and Br₂ were evaporated andthe residue was purified by column chromatography on silica gel(eluent:hexane/CH₂Cl₂—2:1). The product was obtained as a pale orangesolid (0.947 g; 67%).

¹H NMR (500 MHz, CDCl₃) δ 8.07 (d, J=1.55 Hz, 1H); 7.87-7.77 (m, 3H);7.69-7.66 (m, 1H); 7.52-7.46 (m, 2H); 6.25 (d, J=2.10 Hz, 1H); 5.87 (d,J=2.10 Hz, 1H).

¹³C NMR (126 MHz, CDCl₃) δ 135.9, 133.7, 133.2, 131.3, 128.8, 128.1,127.8, 127.1, 126.9, 124.4, 118.2.

HRMS (APCI): calcd. for C₁₂H₁₀Br [M+H]⁺=232.9960; found [M+H]⁺=232.9958.

Preparative Example 2A

A mixture of vinyl bromide from Preparative Example 1 (0.947 g; 4.06mmol), bis(pinacolato)diboron (1.140 g; 4.49 mmol), PPh₃ (0.066 g; 0.25mmol), potassium phenolate (0.809 g; 6.12 mmol) and PdCl₂(PPh₃)₂ (0.089g; 0.13 mmol) in anhydrous toluene (20 mL) was stirred under N₂ at 50°C. for 24 h. The crude mixture was then cooled to 25° C., poured intowater (100 mL) and extracted with EtOAc (3×80 mL). The organic extractswere washed with brine (80 mL), dried over Na₂SO₄, filtered, and thesolvent was evaporated. The obtained oil was purified by columnchromatography on silica gel (eluent:hexane/CH₂Cl₂—2:1) to yield theproduct as a pale orange solid (0.460 g; 40%).

¹H NMR (500 MHz, CDCl₃) δ 7.94 (s, 1H); 7.84-7.75 (m, 3H); 7.61 (dd,J=1.50 Hz, 8.54 Hz, 1H); 7.46-7.38 (m, 2H); 6.20 (d, J=2.29 Hz, 1H);6.14 (d, 2.73 Hz, 1H); 1.35 (s, 12H).

¹³C NMR (126 MHz, CDCl₃) δ 139.1, 133.8, 132.9, 131.4, 128.5, 127.8,127.7, 126.4, 126.0, 125.8, 84.1, 25.1.

HRMS (APCI): calcd. for C₁₈H₂₂BO₂ [M+H]⁺=281.1711; found[M+H]⁺=281.1708.

Preparative Example 2B

A heatgun-dried round bottom flask containing Ni(dppp)Cl₂ (0.251 g; 0.46mmol) was flushed with N₂, anhydrous THF (24 mL) was added, followed bydropwise addition of DIBAL-H (1.0M solution in heptane; 20 mL; 20 mmol)at 25° C. The mixture was cooled to 0° C. and 4-ethynylanisole (2.0 mL;15.4 mmol) was added slowly over 5 min. The resulting black solution wasallowed to warm to 25° C. and stirred for additional 2 h. Then,2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.6 mL; 46.4 mmol)was added dropwise at 0° C. and the resulting reaction mixture wasstirred under N₂ at 80° C. for 15 h. The reaction was then quenched bydropwise addition of water (50 mL) at 0° C., allowed to warm to 25° C.and stirred for additional 1 h. The mixture was poured into saturatedaqueous solution of potassium sodium tartarate (200 mL) and extractedwith Et₂O (3×150 mL). The extracts were washed with brine (200 mL),dried over MgSO₄, filtered and the solvent was evaporated. The resultingoil was purified by column chromatography on silica gel(eluent:hexane/EtOAc—10:1) to yield the product as a pale yellow solid(3.22 g; 80%).

¹NMR (500 MHz, CDCl₃) δ 7.45-7.41 (m, 2H); 6.87-6.82 (m, 2H); 5.99 (d,J=2.65 Hz, 1H); 5.94 (d, J=2.82 Hz, 1H); 3.79 (s, 3H); 1.31 (s, 12H).

¹³C NMR (126 MHz, CDCl₃) δ 159.1, 134.2, 129.2, 128.5, 113.9, 84.0,77.5, 77.2, 77.0, 55.5, 25.0.

HRMS (APCI): calcd. for C₁₅H₂₂BO₃ [M+H]⁺=260.1693; found[M+H]⁺=260.1696.

Preparative Example 2C

By essentially same procedure set forth in Preparative Example 2B, using1-(tert-butyl)-4-ethynylbenzene, the compound given below was prepared.

White solid.

¹H NMR (500 MHz, CDCl₃) δ 7.44 (d, J=8.5 Hz, 2H), 7.35 (d, J=8.5 Hz,2H), 6.08 (d, J=2.8 Hz, 1H), 6.02 (d, J=3.0 Hz, 1H), 1.36-1.30 (m, 21H).

¹³C NMR (126 MHz, CDCl₃) δ 150.0, 138.5, 130.2, 126.9, 125.2, 83.8,34.6, 31.5, 25.0.

HRMS (APCI): calcd. for C₁₈H₂₇BO₂ [M+H]⁺=286.2213; found[M+H]⁺=286.2213.

Preparative Example 3

To a stirred solution of 2-chloro-5-hydroxypyridine (6.0 g, 46.3 mmol)in H₂O (80 mL) were added Na₂CO₃ (10.3 g, 97.3 mmol) and I₂ (11.8 g,46.3 mmol). The resulting mixture was stirred at 25° C. under N₂ for 2h. Then it was neutralized by HCl (1M, approx. 50 mL) to pH=7 andextracted with EtOAc (3×110 mL). The organic extracts were washed withbrine (150 mL), dried over Na₂SO₄, filtered, and the solvent wasevaporated. The product was obtained as a pale yellow solid (11.1 g,94%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.10 (s, 1H); 7.30 (d, J=8.40 Hz, 1H); 7.18(d, J=8.40 Hz, 1H).

¹³C NMR (126 MHz, DMSO-d₆) δ 153.9, 138.1, 124.0, 123.9, 107.7.

HRMS (APCI): calcd. for C₅H₄ClINO [M+H]⁺=255.9021; found[M+H]⁺=255.9018.

Preparative Example 4A

To a mixture of vinyl boronate from Preparative Example 2A (0.460 g;1.64 mmol), pyridinol from Preparative Example 3 (0.349 g; 1.37 mmol),K₃PO₄ (1.196 g; 5.64 mmol) and PdCl₂.dppf (0.063 g; 0.068 mmol) wereadded under N₂ 1,2-dimethoxyethane (8 mL) and water (2 mL). Theresulting reaction mixture was refluxed for 15 h. Then it was cooled to25° C., poured into brine (80 mL) and extracted with CH₂Cl₂ (3×60 mL).The organic extracts were dried over Na₂SO₄, filtered, and the solventwas evaporated. The residue was purified by column chromatography onsilica gel (eluent:CH₂Cl₂) to yield the product as a pale yellow solid(0.105 g; 27%).

¹H NMR (500 MHz, CDCl₃) δ 7.85-7.75 (m, 3H); 7.72 (d, J=1.33 Hz, 1H);7.52 (dd, J=1.86 Hz, 8.57 Hz, 1H); 7.50-7.45 (m, 2H); 7.26-7.22 (m, 2H);6.06 (s, 1H); 5.79 (s, 1H); 5.07 (s, 1H).

¹³C NMR (126 MHz, CDCl₃) δ 149.6, 145.6, 143.8, 142.3, 134.9, 133.7,133.6, 129.1, 128.7, 127.9, 127.4, 127.0, 126.9, 126.8, 125.0, 124.5,120.9.

Preparative Example 4B

By essentially same procedure set forth in Preparative Example 4A, using1-phenylvinylboronic acid pinacol ester instead of vinyl boronate fromPreparative Example 2A, the compound given below was prepared.

¹H NMR (500 MHz, CDCl₃) δ 7.39-7.31 (m, 5H); 7.23-7.18 (m, 2H); 5.93 (d,J=0.73 Hz, 1H); 5.71 (d, J=0.68 Hz, 1H); 5.00 (brs, 1H).

¹³C NMR (126 MHz, CDCl₃) δ 149.5, 145.5, 143.8, 142.2, 137.6, 129.3,129.3, 127.3, 127.2, 125.0, 120.1.

HRMS (APCI): calcd. for C₁₃H₁₁ClNO [M+H]⁺=232.0524; found[M+H]⁺=232.0525.

Preparative Example 4C

By essentially same procedure set forth in Preparative Example 4A, usingthe vinyl boronate from Preparative Example 2B, the compound given belowwas prepared.

¹H NMR (500 MHz, CDCl₃) δ 7.30-7.25 (m, 2H); 7.23-7.17 (m, 2H);6.89-6.85 (m, 2H); 5.83 (d, J=0.65 Hz, 1H); 5.59 (d, J=0.52 Hz, 1H);5.10 (brs, 1H); 3.80 (s, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 160.6, 149.5, 145.8, 143.1, 142.1, 129.8,128.6, 127.2, 124.9, 118.3, 114.7, 55.6.

HRMS (APCI): calcd. for C₁₄H₁₃ClNO₂ [M+H]⁺=262.0629; found[M+H]⁺=262.0631.

Preparative Example 4D

The product from Preparative Example 3 (1.16 g, 4.53 mmol), the productfrom Preparative Example 2C (1.18 g, 4.12 mmol), K₃PO₄ (3.5 g, 16.5mmol), DMF (5.5 mL) and PdCl₂(dppf) (150 mg, 0.206 mmol) were placedinto a 50 mL round bottom flask and the mixture was stirred under N₂ at80° C. for 14 h. The solvent was evaporated and the residue was loadedon silica gel and purified by column chromatography (CH₂Cl₂/hexane;4:1). The product was obtained as a white solid (492 mg, 41%).

¹H NMR (500 MHz, CDCl₃) δ 7.42-7.37 (m, 2H), 7.32-7.28 (m, 2H),7.24-7.20 (m, 2H), 5.92 (d, J=0.8 Hz, 1H), 5.69 (d, J=0.7 Hz, 1H), 5.04(s, 1H), 1.32 (s, 9H).

¹³C NMR (126 MHz, CDCl₃) δ 152.5, 149.4, 145.5, 143.4, 142.0, 134.3,127.1, 126.8, 126.2, 124.7, 119.3, 34.8, 31.4.

HRMS (APCI): calcd. for C₁₇H₁₈ClNO [M+H]⁺=288.1150; found[M+H]⁺=288.1148.

Preparative Example 4E

2-(3,3-dimethylbut-1-en-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(400 mg, 1.90 mmol), DMF (7 mL), K₃PO₄ (1.2 g, 5.72 mmol), the productfrom Preparative Example 3 (584 mg, 2.28 mmol) and PdCl₂(dppf) (69 mg,95 μmol) were placed into a 25 mL round bottom flask. The mixture wasstirred under N₂ at 80° C. for 9 h. Then, additional PdCl₂(dppf) (47 mg,64 μmol) was added and the mixture was stirred at 90° C. for additional45 h. The solvent was evaporated and the residue was loaded on silicagel and purified by column chromatography (from EtOAc/hexane; 1:20 toEtOAc). The product was obtained as a white solid (40 mg, 10%) oflimited stability.

¹H NMR (300 MHz, CDCl₃) δ 7.22 (d, J=8.5 Hz, 1H), 7.12 (d, J=8.5 Hz,1H), 5.62 (s, 1H), 5.35 (s, 1H), 5.15 (s, 1H), 1.20 (s, 9H).

¹³C NMR (126 MHz, CDCl₃) δ 153.4, 148.6, 147.7, 140.8, 125.8, 123.8,116.0, 37.2, 29.6.

HRMS (APCI): calcd. for C₁₁H₁₄ClNO [M+H]⁺=212.0837; found[M+H]⁺=212.0835.

Preparative Example 5A

A mixture of the product from Preparative Example 4A (0.105 g; 0.37mmol), copper(I) acetate (0.029 g; 0.24 mmol), 8-hydroxyquinoline (0.037g; 0.25 mmol) and K₂CO₃ (0.067 g; 0.48 mmol) in anhydrousN,N-dimethylacetamide (1.5 mL) was stirred under O₂ at 140° C. for 18 h.Then the reaction mixture was concentrated under reduce pressure, theresidual oil was poured into water (50 mL) and extracted with EtOAc(3×30 mL). The organic extracts were washed with brine (40 mL), driedover MgSO₄, filtered and the solvent was evaporated. The resultingresidue was purified by column chromatography on silica gel(eluent:hexane/CH₂Cl₂—1:1) to yield the product as a pale solid product(0.037 g; 36%).

¹H NMR (500 MHz, CDCl₃) δ 8.67 (s, 1H); 8.23 (s, 1H); 8.01-7.93 (m, 2H);7.90 (d, J=8.53 Hz, 1H); 7.85-7.82 (m, 1H); 7.75 (d, J=8.60 Hz, 1H);7.53-7.45 (m, 2H); 7.29 (d, J=8.59 Hz, 1H).

¹³C NMR (126 MHz, CDCl₃) δ 148.0, 147.3, 146.4, 146.0, 133.9, 133.2,128.7, 128.7, 127.9, 127.3, 126.5, 126.4, 126.4, 124.9, 121.7, 121.3,119.9.

HRMS (APCI): calcd. for C₁₇H₁₀ ClNO [M+H]⁺=280.0524; found[M+H]⁺=280.0526.

Preparative Example 5B

By essentially same procedure set forth in Preparative Example 5A, usingproduct from Preparative Example 41B, the compound given below wasprepared.

¹H NMR (500 MHz, CDCl₃) δ 8.12 (s, 1H); 8.04-7.99 (m, 2H); 7.73 (d,J=8.61 Hz, 1H); 7.49-7.43 (m, 2H); 7.37-7.32 (m, 1H); 7.27 (d, J=8.60Hz, 1H).

¹³C NMR (126 MHz, CDCl₃) δ 147.9, 147.3, 146.1, 145.9, 129.9, 129.1,128.2, 127.3, 121.8, 121.3, 119.8.

HRMS (APCI): calcd. for C₁₃H₉ClNO [M+H]⁺=230.0367; found[M+H]⁺=230.0365.

Preparative Example 5C

By essentially same procedure set forth in Preparative Example 5A, usingthe product from Preparative Example 4C, the compound given below wasprepared.

¹H NMR (500 MHz, CDCl₃) δ 8.05 (s, 1H); 7.97-7.93 (m, 2H); 7.71 (d,J=8.59 Hz, 1H); 2.25 (d, J=8.59 Hz, 1H); 7.01-6.97 (m, 2H); 3.84 (s,3H).

¹³C NMR (126 MHz, CDCl₃) δ 159.7, 147.9, 147.1, 146.0, 145.2, 128.5,122.4, 121.5, 121.2, 119.6, 114.6, 55.6.

HRMS (APCI): calcd. for C₁₄H₁₁ClNO₂ [M+H]⁺=260.0473; found[M+H]⁺=260.0469.

Preparative Example 5D

The product from Preparative Example 4D (470 mg, 1.63 mmol), Cu(OAc)₂(148 mg, 0.816 mmol), quinolin-8-ol (118 mg, 0.816 mmol), K₂CO₃ (248 mg,1.79 mmol) were placed into a 50 mL round bottom flask. The flask wasfilled with O₂. Then, N,N-dimethylacetamide (4 mL) was added and themixture was stirred at 140° C. for 75 min. The solvent was evaporatedand the residue was loaded on silica gel and purified by columnchromatography (CH₂Cl₂/hexane; 1:1). The product was obtained as anorange solid (378 mg, 74%).

¹H NMR (500 MHz, CDCl₃) δ 8.11 (s, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.74 (d,J=8.6 Hz, 1H), 7.51 (d, J=8.5 Hz, 2H), 7.28 (d, J=8.6 Hz, 1H), 1.36 (s,9H).

¹³C NMR (126 MHz, CDCl₃) δ 151.2, 147.8, 147.1, 146.0, 145.7, 127.0,126.8, 126.0, 121.7, 121.1, 119.6, 34.8, 31.5.

HRMS (APCI): calcd. for C₁₇H₁₆ClNO [M+H]⁺=286.0993; found[M+H]⁺=286.0991.

Preparative Example 5E

By essentially same procedure set forth in Preparative Example 5D, usingthe product from Preparative Example 4E, the compound given below wasprepared.

White solid.

¹H NMR (500 MHz, CDCl₃) δ 7.63 (d, J=8.6 Hz, 1H), 7.56 (s, 1H), 7.17 (d,J=8.6 Hz, 1H), 1.48 (s, 9H).

¹³C NMR (126 MHz, CDCl₃) δ 147.7, 147.0, 145.8, 144.3, 131.0, 120.6,118.8, 31.0, 29.6.

HRMS (APCI): calcd. for [M+H]⁺=210.0680; found [M+H]⁺=210.0682.

Preparative Example 6A

To a mixture of the product from Preparative Example 5B (0.052 g; 0.23mmol), 1-methylpyrazole-4-boronic acid pinacol ester (0.059 g; 0.28mmol), K₃PO₄ (0.227 g; 1.07 mmol) and PdCl₂(dppf) (0.011 g; 0.015 mmol)were added under N₂ 1,2-dimethoxyethane (2 mL) and water (0.5 mL). Theresulting reaction mixture was refluxed for 18 h. Then it was cooled to25° C., diluted with EtOAc (10 mL), poured into brine (25 mL) andextracted with EtOAc (3×10 mL). The organic extracts were dried overNa₂SO₄, filtered, and the solvent was evaporated. The residue waspurified by column chromatography on silica gel(eluent:CH₂Cl₂/EtOAc—2:1) to yield the product as a pale orange solid(0.051 g; 81%).

¹H NMR (500 MHz, CDCl₃) δ 8.17-8.13 (m, 2H); 8.09 (s, 1H); 7.99 (d,J=5.58 Hz, 2H); 7.72 (d, J=8.61 Hz, 1H); 7.50-7.7.44 (m, 2H); 7.42 (d,J=8.60 Hz; 1H); 7.37-7.32 (m, 1H); 3.96 (s, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 148.9, 147.7, 145.9, 145.2, 137.7, 131.0,129.1, 128.9, 127.8, 127.3, 124.4, 121.7, 119.2, 115.8, 39.4.

HRMS (APCI): calcd. for C₁₇H₁₄N₃O [M+H]⁺=276.1131; found[M+H]⁺=276.1128.

Preparative Example 6B

To a mixture of the product from Preparative Example 5B (0.311 g; 1.36mmol), phenylboronic acid pinacol ester (0.225 g; 1.85 mmol), K₃PO₄(1.20 g; 5.64 mmol) and PdCl₂.dppf (0.062 g; 0.084 mmol) were addedunder N₂ 1,2-dimethoxyethane (8 mL) and water (2 mL). The reactionmixture was refluxed under N₂ for 19 h. Then it was cooled to 25° C.,diluted with EtOAc (40 mL), poured into brine (50 mL) and extracted withEtOAc (3×40 mL). The organic extracts were dried over Na₂SO₄, filtered,and the solvent was evaporated. The residue was purified by columnchromatography on silica gel (eluent:hexane/EtOAc—5:1) to yield theproduct as a pale yellow wax (0.262 g; 71%).

¹H NMR (500 MHz, CDCl₃) δ 8.26-8.19 (m, 2H); 8.17-8.10 (m, 3H); 7.83 (d,J=8.66 Hz, 1H); 7.73 (d, J=8.67 Hz, 1H); 7.54-7.46 (m, 4H); 7.45-7.33(m, 2H).

¹³C NMR (126 MHz, CDCl₃) δ 154.3, 148.3, 146.1, 145.4, 140.0, 130.9,129.0, 128.9, 128.8, 127.9, 127.4, 127.3, 122.0, 119.2, 116.8.

HRMS (APCI): calcd. for C₁₉H₁₄NO [M+H]⁺=272.1070; found [M+H]⁺=272.1074.

Preparative Example 6C

To a mixture of the product from Preparative Example 5B (0.078 g; 0.34mmol), 1-Boc-pyrazole-4-boronic acid pinacol ester (0.122 g; 0.42 mmol),K₃PO₄ (0.282 g; 1.33 mmol) and palladium catalyst PdCl₂.dppf (0.018 g;0.024 mmol) were added under N₂ 1,2-dimethoxyethane (2 mL) and water(0.5 mL). The reaction mixture was refluxed under N₂ for 15 h. Then itwas cooled to 25° C., diluted with EtOAc (15 mL), poured into brine (25mL) and extracted with EtOAc (3×15 mL). The organic extracts were driedover Na₂SO₄, filtered, and the solvent was evaporated. The residue waspurified by column chromatography on silica gel(eluent:hexane/EtOAc—2:1) to yield the product as a pale yellow solid(0.047 g; 38%).

¹H NMR (300 MHz, CDCl₃) δ 8.27 (s, 1H); 8.18-8.11 (m, 3H); 7.78 (d,J=8.59 Hz, 1H); 7.53-7.44 (m, 3H); 7.40-7.32 (m, 1H); 1.68 (s, 9H).

Preparative Example 6D

To a mixture of the product from Preparative Example 5B (0.088 g; 0.38mmol), 3-pyridineboronic acid pinacol ester (0.098 g; 0.48 mind), K₃PO₄(0.336 g; 1.58 mmol) and palladium catalyst PdCl₂.dppf (0.019 g; 0.026mmol) were added under N₂ 1,2-dimethoxyethane (2 mL) and water (0.5 mL).The reaction mixture was refluxed under N₂ for 19 h. Then it was cooledto 25° C., diluted with EtOAc (15 mL), poured into brine (25 mL) andextracted with EtOAc (3×15 mL). The organic extracts were dried overNa₂SO₄, filtered, and the solvent was evaporated. The residue waspurified by column chromatography on silica gel(eluent:CH₂Cl₂/MeOH—15:1) to yield the product as a pale brown solid(0.087 g; 83%).

¹H NMR (500 MHz, CDCl₃) δ 9.43 (brs, 1H); 8.73 (brs, 1H); 8.44 (d,J=7.88 Hz, 1H); 8.23-8.15 (m, 3H); 7.87 (d, J=8.57 Hz, 1H); 7.74 (d,J=8.61 Hz, 1H); 7.53-7.34 (m, 4H).

¹³C NMR (126 MHz, CDCl₃) δ 151.5, 149.6, 148.7, 148.6, 146.6, 145.8,1358, 134.8, 130.6, 129.1, 128.1, 127.3, 124.2, 122.0, 119.5, 116.7.

HRMS (APCI): calcd. for C₁₈H₁₃N₂O [M+H]⁺=273.1022; found[M+H]⁺=273.1022.

Preparative Example 7A

To a mixture of Preparative Example 5A (0.053 g; 0.19 mmol),1-methylpyrazole-4-boronic acid pinacol ester (0.048 g; 0.23 mmol),K₃PO₄ (0.177 g; 0.83 mmol) and PdCl₂.dppf (0.010 g; 0.014 mmol) wereadded under N₂ 1,2-dimethoxyethane (2 mL) and water (0.5 mL). Thereaction mixture was refluxed for 19 h. Then it was cooled to 25° C.,diluted with EtOAc (10 mL), poured into brine (25 mL) and extracted withEtOAc (3×10 mL). The organic extracts were dried over Na₂SO₄, filteredand the solvent was evaporated. The residue was purified by columnchromatography on silica gel (eluent:EtOAc/MeOH—20:1) to yield theproduct as a pale yellow solid (0.049 g; 79%).

¹H NMR (500 MHz, CDCl₃) δ 8.86 (s, 1H); 8.21 (s, 1H); 8.11-7.99 (m, 3H);7.97-7.89 (m, 2H); 7.85 (d, J=7.82 Hz, 1H); 7.76 (d, J=8.26 Hz, 1H);7.54-7.42 (m, 3H); 3.99 (s, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 148.9, 147.8, 145.9, 145.6, 137.8, 133.9,133.1, 129.2, 128.6, 128.5, 128.3, 128.0, 126.5, 126.2, 125.1, 124.4,121.6, 119.4, 116.0, 39.5.

HRMS (APCI): calcd. for C₂₁H₁₆N₃O [M+H]⁺=326.1288; found[M+H]⁺=326.1284.

Preparative Example 7B

Tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(77 mg, 0.26 mmol), the product from Preparative Example 5A (61 mg, 0.22mmol), K₃PO₄ (180 mg, 0.85 mmol), 1,2-dimethoxyethane (2 mL), H₂O (0.5mL) and PdCl₂(dppf) (1.8 mg, 0.008 mmol) were added into a 25 mL roundbottom flask. The mixture was refluxed under N₂ for 18 h, then saturatedaqueous solution of NH₄Cl (15 mL) was added, the mixture was extractedwith EtOAc (10 mL) and then with CH₂Cl₂ (2×20 mL). The organic extractswere dried over Na₂SO₄, filtered, and the solvents were evaporated. Theresidue was loaded on silica gel and purified by column chromatography(EtOAc/hexane; 5:4) to afford the product as a light yellow solid (47mg, 69%).

¹H NMR (500 MHz, CDCl₃) δ 8.94 (s, 1H), 8.32-8.20 (m, 3H), 8.11 (d,J=8.6 Hz, 1H), 8.00-7.91 (m, 2H), 7.87 (d, J=7.8 Hz, 1H), 7.81 (d, J=8.6Hz, 1H), 7.56-7.47 (m, 3H).

¹H NMR (300 MHz, DMSO-d6) δ 13.04 (b, 1H), 9.12 (s, 1H), 8.95 (s, 1H),8.52-8.20 (m, 3H), 8.14-7.99 (m, 3H), 7.99-7.90 (m, 1H), 7.78 (d, J=8.7Hz, 1H), 7.63-7.49 (m, 2H).

¹³C NMR (126 MHz, CDCl₃) δ 148.6, 147.8, 146.0, 145.5, 133.8, 133.0,128.5, 128.4, 128.2, 127.9, 126.4, 126.1, 124.9, 121.5, 119.2, 116.1.

HRMS (APCI): calcd. for C₂₀H₁₃N₃O [M+H]⁺=312.1131; found[M+H]⁺=312.1129.

Preparative Example 7C

1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(41 mg, 0.17 mmol), the product from Preparative Example 5A (40 mg, 0.14mmol), K₃PO₄ (91 mg, 0.43 mmol), 1,2-dimethoxyethane (2 mL), H₂O (0.5mL) and PdCl₂(dppf) (3.1 mg, 4.3 μmol) were added into a 25 mL roundbottom flask and the mixture was refluxed under N₂ for 2 h. The solventwas evaporated and the residue was loaded on silica gel and purified bycolumn chromatography (EtOAc/hexane; 1:1) to yield the product as alight yellow wax (40 mg, 79%).

¹H NMR (500 MHz, CDCl₃) δ 8.91 (s, 1H), 8.23 (s, 1H), 8.13-8.07 (m, 3H),7.98-7.92 (m, 2H), 7.87 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H),7.55-7.47 (m, 3H), 4.60 (sep, J=13.4, 6.7 Hz, 1H), 1.62 (s, 3H), 1.60(s, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 149.1, 147.6, 145.9, 145.3, 137.3, 133.8,133.0, 128.4, 128.4, 128.3, 127.8, 126.3, 126.0, 125.4, 125.0, 123.6,121.5, 119.2, 115.8, 54.2, 23.1.

HRMS (APCI): calcd. for C₂₃H₁₉N₃O [M+H]⁺=354.1601; found[M+H]⁺=354.1596.

Preparative Example 7D

Tert-butyl3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(55 mg, 0.17 mmol), the product from Preparative Example 5A (40 mg, 0.14mmol), K₃PO₄ (91 mg, 0.43 mmol), 1,2-dimethoxyethane (2 mL), H₂O (0.5mL) and PdCl₂(dppf) (3.1 mg, 4.3 μmol) were added into a 25 mL roundbottom flask and the mixture was refluxed under N₂ for 24 h. Then,additional tert-butyl3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(30 mg, 0.09 mmol) and PdCl₂(dppf) (4 mg, 5.4 μmol) were added and themixture was refluxed under N₂ for additional 24 h. The solvent wasevaporated and the residue was loaded on silica gel and purified bycolumn chromatography (EtOAc/MeOH; 30:1) and then re-chromatographed(EtOAc/hexane; 1:1). So obtained material was purified by preparativeTLC (EtOAc/hexane; 1:1) and then by another preparative TLC(CH₂Cl₂/MeOH; 15:1). The product was obtained as a colorless wax (7.2mg, 29% yield).

¹H NMR (300 MHz, CDCl₃) δ 8.99 (s, 1H), 8.28 (s, 1H), 8.06 (dd, J=8.6,1.6 Hz, 1H), 7.99-7.79 (m, 4H), 7.57-7.43 (m, 2H), 7.39 (d, J=8.6 Hz,1H), 2.62 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 150.4, 147.0, 145.8, 145.3, 144.7, 143.4,133.8, 132.9, 128.4, 128.3, 128.2, 127.8, 126.4, 126.3, 126.0, 124.7,121.6, 118.9, 118.8, 118.1, 12.9, 12.3.

HRMS (APCI): calcd. for C₂₂H₁₇N₃O [M+H]⁺=340.1444; found[M+H]⁺=340.1441.

Preparative Example 7E

(1,3,5-trimethyl-1H-pyrazol-4-yl)boronic acid (33 mg, 0.21 mmol), theproduct from Preparative Example 5A (50 mg, 0.18 mmol), K₃PO₄ (133 mg,0.63 mmol), 1,2-dimethoxyethane (2.4 mL), H₂O (0.6 mL) and PdCl₂(dppf)(6.5 mg, 8.9 mmol) were added into a 10 mL round bottom flask and themixture was refluxed under N₂ for 18 h. Additional PdCl₂(dppf) (4 mg,5.4 μmol) and K₃PO₄ (118 mg, 0.56 mmol) were added and the mixture wasrefluxed for additional 12 h. Then, another portion of PdCl₂(dppf) (4mg, 5.4 μmol) was added and the mixture was refluxed for additional 10h. The solvent was evaporated and the residue was loaded on silica geland purified by column chromatography (EtOAc/hexane; from 1:1 to 2:1)and then by preparative TLC (CH₂Cl₂/MeOH; 15:1) to yield the product asa colorless wax (5 mg, 8%).

¹H NMR (500 MHz, CDCl₃) δ 8.99 (s, 1H), 8.28 (s, 1H), 8.06 (dd, J=8.5,1.7 Hz, 1H), 7.94-7.88 (m, 2H), 7.88-7.82 (m, 2H), 7.54-7.44 (m, 2H),7.35 (d, J=8.6 Hz, 1H), 3.85 (s, 3H), 2.59 (s, 3H), 2.51 (s, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 150.7, 147.0, 145.9, 145.8, 145.3, 138.1,133.9, 132.9, 128.4, 128.3, 128.2, 127.8, 126.4, 126.3, 126.0, 124.7,121.6, 119.2, 118.9, 118.8, 36.1, 13.7, 11.2.

HRMS (APCI): calcd. for C₂₃H₁₉N₃O [M+H]⁺=354.1601; found M+H]⁺=354.1599.

Preparative Example 7F

A mixture of 5-thiazole boronic acid MIDA ester (69 mg, 0.29 mmol), theproduct from Preparative Example 5A (62 mg, 0.22 mmol), K₃PO₄ (165 mg,0.78 mmol), 1,2-dimethoxyethane (2 mL), H₂O (0.5 mL) and PdCl₂(dppf)(8.1 mg, 11 μmol) was stirred at 60° C. under N₂ for 2 h and then at 80°C. for 7 h. Additional PdCl₂(dppf) (4 mg, 5.4 μmol), the mixture wasrefluxed for 27 h, then additional PdCl₂(PPh₃)₂ (4 mg, 5.7 μmol) wasadded and the mixture was refluxed for additional 24 h. Then, additionalPd(PPh₃)₄ (5 mg, 4.3 μmol) and 5-thiazole boronic acid MIDA ester (20mg, 0.083 mmol) were added and the mixture was refluxed for additional24 h. The solvent was evaporated and the residue was loaded on silicagel and purified by column chromatography (EtOAc/hexane; from 1:2 to1:1) and then by preparative TLC (EtOAc/hexane; 1:1). The product wasobtained as a light yellow solid (7 mg, 10%).

¹H NMR (300 MHz, CDCl₃) δ 8.98 (s, 1H), 8.88 (s, 1H), 8.41 (s, 1H), 8.30(s, 1H), 8.07 (dd, J=8.6, 1.7 Hz, 1H), 8.03-7.84 (m, 4H), 7.74 (d, J=8.6Hz, 1H), 7.58-7.48 (m, 2H).

¹³C NMR (126 MHz, CDCl₃) δ 154.4, 148.4, 147.0, 146.3, 146.1, 141.4,139.7, 133.8, 133.0, 128.6, 128.5, 127.8, 127.7, 126.5, 126.5, 126.3,124.6, 121.4, 119.5, 116.0.

HRMS (APCI): calcd. for C₂₀H₁₂N₂OS [M+H]⁺=329.0743; found[M+H]⁺=329.0747.

Preparative Example 8A

To a freshly prepared solution of(S)-1-[(R_(P))-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine(0.013 g; 0.023 mmol) and Pd(OAc)₂ (0.007 g; 0.030 mmol) in anhydrous1,2-dimethoxyethane (2 mL) were added the product from PreparativeExample 5B (0.053 g; 0.23 mmol), t-BuOK (0.036 g; 0.32 mmol) and3-methoxy-4-(4-methylpiperazin-1-yl)aniline (0.064 g; 0.29 mmol) and theresulting mixture was stirred under N₂ at 100° C. for 16 h. Then it wascooled to 25° C., diluted with EtOAc (10 mL), poured into brine (25 mL)and extracted with EtOAc (3×10 mL). The organic extracts were dried overMgSO₄, filtered and the solvent was evaporated. The residue was purifiedby column chromatography on silica gel (eluent:CH₂Cl₂/7N NH₃ inMeOH—30:1) to yield the product as a dark orange semi-solid (0.079 g;83%).

¹H NMR (500 MHz, CDCl₃) δ 8.05-8.02 (m, 2H); 7.99 (s, 1H); 7.59 (d,J=8.93 Hz, 1H); 7.44-7.39 (m, 2H); 7.33-7.27 (m, 2H); 6.91-6.81 (m, 2H);6.70 (d, J=8.94 Hz, 1H); 6.49 (brs, 1H); 3.80 (s, 3H); 3.10 (s, 4H);2.68 (s, 4H); 2.38 (s, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 154.0, 153.1, 144.6, 143.7, 137.3, 136.6,131.3, 128.9, 127.6, 127.2, 121.5, 121.0, 118.9, 112.3, 106.5, 104.8,55.8, 55.6, 50.9, 46.2.

HRMS (APCI): calcd. for C₂₅H₂₇N₄O₂ [M+H]⁺=415.2129; found[M+H]⁺=415.2129.

Preparative Example 8B

To a freshly prepared solution of(S)-1-[(R_(P))-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine(0.007 g; 0.012 mmol) and Pd(OAc)₂ (0.004 g; 0.018 mmol) in anhydrous1,2-dimethoxyethane (2 mL) were added the product from PreparativeExample 5B (0.067 g; 0.29 mmol), t-BuOK (0.041 g; 0.43 mmol) and4-morpholinoaniline (0.062 g; 0.35 mmol) and the resulting mixture wasstirred under N₂ at 100° C. for 14 h. Then it was cooled to 25° C.,diluted with EtOAc (10 mL), poured into brine (25 mL) and extracted withEtOAc (3×10 mL). The organic extracts were dried over MgSO₄, filtered,and the solvent was evaporated. The residue was purified by columnchromatography on silica gel (eluent:CH₂Cl₂/MeOH—50:1) to yield theproduct as an orange solid (0.062 g; 58%).

¹H NMR (500 MHz, DMSO-d6) δ 8.92 (s, 1H); 8.59 (s, 1H); 8.25-8.20 (m,2H); 7.84 (d, J=9.01 Hz, 1H); 7.72-7.66 (m, 2H); 7.54-7.47 (m, 2H);7.38-7.31 (m, 1H); 6.98-6.91 (m, 2H); 6.79 (d, J=9.04 Hz, 1H); 3.78-3.72(m, 4H); 3.08-3.03 (m, 4H).

¹³C NMR (126 MHz, DMSO-d6) δ 153.6, 145.3, 145.0, 143.0, 141.6, 134.6,131.0, 128.5, 127.0, 126.2, 121.0, 119.7, 118.9, 115.8, 107.7, 66.1,49.4.

HRMS (APCI): calcd. for C₂₃H₂₂N₃O₂ [M+H]⁺=372.1707; found[M+H]⁺=372.1704.

Preparative Example 8C

To a freshly prepared solution of(S)-1-[(R_(P))-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine(0.008 g; 0.014 mmol) and Pd(OAc)₂ (0.010 g; 0.042 mmol) in anhydrous1,2-dimethoxyethane (2 mL) were added the product from PreparativeExample 5B (0.061 g; 0.26 mmol), t-BuOK (0.038 g; 0.40 mmol) and4-(4-methyl-1-piperazinyl)aniline (0.057 g; 0.30 mmol) and the resultingmixture was stirred under N₂ at 100° C. for 19 h. Then it was cooled to25° C., diluted with EtOAc (15 mL), poured into brine (25 mL) andextracted with EtOAc (3×15 mL). The organic extracts were dried overMgSO₄, filtered and the solvent was evaporated. The resulting residuewas purified by column chromatography on silica gel (eluent:CH₂Cl₂/7NNH₃ in MeOH—15:1) to yield the product as a pale brown solid (0.069 g;68%).

¹H NMR (500 MHz, CDCl₃) δ 8.08-8.04 (m, 2H); 7.99 (s, 1H); 7.56 (d,J=8.96 Hz, 1H); 7.46-7.41 (m, 2H); 7.37-7.28 (m, 3H); 6.93 (d, J=5.55Hz, 2H); 6.66 (d, J=8.61 Hz, 1H); 6.41 (brs, 1H); 3.18 (brs, 4H);2.63-2.57 (m, 4H); 2.36 (s, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 147.8, 144.5, 143.8, 134.0, 131.3, 128.9,127.5, 127.2, 122.8, 122.7, 121.3, 120.9, 117.5, 105.4, 55.4, 50.0,46.3.

HRMS (APCI): calcd. for C₂₄H₂₅N₄O [M+H]⁺=385.2023; found[M+H]⁺=385.2030.

Preparative Example 8D

To a freshly prepared solution of(S)-1-[(R_(P))-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine(0.009 g; 0.016 mmol) and Pd(OAc)₂ (0.015 g; 0.068 mmol) in anhydrous1,2-dimethoxyethane (2 mL) were added the product from PreparativeExample 5B (0.054 g; 0.23 mmol), t-BuOK (0.033 g; 0.34 mmol) and4-aminopyridine (0.024 g; 0.26 mmol) and the resulting mixture wasstirred under N₂ at 100° C. for 14 h. Then it was cooled to 25° C.,diluted with EtOAc (10 mL), poured into brine (25 mL) and extracted withEtOAc (3×10 mL). The organic extracts were dried over MgSO₄, filteredand the solvent was evaporated. The residue was purified by columnchromatography on silica gel (eluent:CH₂Cl₂/7N NH₃ in MeOH—10:1) toyield the product as a pale yellow solid (0.034 g; 50%).

¹H NMR (500 MHz, DMSO-d6) δ 9.71 (s, 1H); 8.71 (s, 1H); 8.35 (d, J=5.44Hz, 2H); 8.19 (d, J=7.31, 2H); 8.02 (d, J=8.93 Hz, 1H); 7.77 (d, J=5.66Hz, 2H); 7.58-7.50 (m, 3H); 7.41-7.35 (m, 1H); 6.98 (d, J=8.94 Hz, 1H).

¹³C NMR (126 MHz, DMSO-d6) δ 152.0, 149.7, 147.8, 145.9, 143.8, 141.8,130.5, 128.6, 127.3, 126.3, 121.5, 120.0, 111.3, 109.2.

HRMS (APCI): calcd. for C₁₈H₁₄N₃O [M+H]⁺=288.1131; found[M+H]⁺=288.1131.

Preparative Example 8E

To a freshly prepared solution of(S)-1-[(R_(P))-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine(0.011 g; 0.020 mmol) and palladium catalyst Pd(OAc)₂ (0.008 g; 0.033mmol) in anhydrous 1,2-dimethoxyethane (2 mL) were added the productfrom Preparative Example 5B (0.053 g; 0.23 mmol), t-BuOK (0.032 g; 0.34mmol) and aniline (0.025 mL; 0.27 mmol) and the resulting mixture wasstirred under N₂ at 100° C. for 15 h. Then it was cooled to 25° C.,diluted with EtOAc (10 mL), poured into brine (25 mL) and extracted withEtOAc (3×10 mL). The organic extracts were dried over MgSO₄, filteredand the solvent was evaporated. The residue was purified by columnchromatography on silica gel (eluent:hexane/EtOAc—5:1) to yield theproduct as a brownish semi-solid (0.050 g; 76%).

¹H NMR (500 MHz, CDCl₃) δ 8.08-8.04 (m, 2H); 8.02 (s, 1H); 7.64 (d,J=8.96 Hz, 1H); 7.49-7.43 (m, 4H); 7.37-7.29 (m, 3H); 7.07-7.00 (m, 1H);6.81 (d, J=8.96 Hz, 1H).

¹³C NMR (126 MHz, CDCl₃) δ 153.4, 144.8, 144.7, 141.2, 130.9, 129.4,129.0, 127.8, 127.2, 122.7, 121.3, 119.9, 106.5.

HRMS (APCI): calcd. for C₁₉H₁₅N₂O [M+H]⁺=287.1179; found[M+H]⁺=287.1180.

Preparative Example 8F

To a solution of the product from Preparative Example 5B (0.045 g; 0.20mmol), (R)-BINAP (0.017 g; 0.027 mmol), Pd₂(dba)₃ (0.014 g; 0.015 mmol)and t-BuOK (0.033 g; 0.29 mmol) in anhydrous toluene (2 mL) was addedN,N-dimethylethylenediamine (0.022 mL; 0.20 mmol) and the resultingmixture was stirred under N₂ at 80° C. for 20 h. Then it was cooled to25° C., diluted with EtOAc (10 mL), poured into water (25 mL) andextracted with EtOAc (3×10 mL). The organic extracts were washed withbrine (15 mL), dried over MgSO₄, filtered and the solvent wasevaporated. The residue was purified by preparative TLC(eluent:CH₂Cl₂/7N NH₃ in MeOH—17:1) to yield the product as an orangewax (0.024 g; 43%).

¹H NMR (500 MHz, CDCl₃) δ 8.13-8.08 (m, 2H); 7.96 (s, 1H); 7.51 (d,J=8.93 Hz, 1H); 7.45-7.39 (m, 2H); 7.32-7.26 (m, 1H); 6.39 (d, J=8.93Hz, 1H); 5.04-4.95 (m, 1H); 3.50 (dd, J=5.71 Hz, 11.41 Hz, 2H); 2.60 (t,J=6.06 Hz, 2H); 2.29 (s, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 156.9, 143.9, 143.8, 143.5, 131.7, 128.8,127.3, 127.0, 121.1, 120.7, 105.4, 58.6, 45.6, 40.1.

HRMS (APCI): calcd. for C₁₇H₂₀N₃O [M+H]⁺=282.1601; found[M+H]⁺=282.1600.

Preparative Example 8G

To a freshly prepared solution of(S)-1-[(R_(P))-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine(0.011 g; 0.023 mmol) and Pd(OAc)₂ (0.007 g; 0.030 mmol) in anhydrous1,2-dimethoxyethane (2 mL) were added the product from PreparativeExample 5C (0.054 g; 0.22 mmol), t-BuONa (0.030 g; 0.31 mmol) and3-methoxy-4-(4-methylpiperazin-1-yl)aniline (0.056 g; 0.25 mmol) and theresulting mixture was stirred under N₂ at 100° C. for 18 h. Then it wascooled to 25° C., diluted with EtOAc (10 mL), poured into brine (25 mL)and extracted with EtOAc (3×10 mL). The organic extracts were dried overMgSO₄, filtered, and the solvent was evaporated. The residue waspurified by column chromatography on silica gel (eluent:CH₂Cl₂/7N NH₃ inMeOH—17:1) to yield the product as a pale orange foam (0.041 g; 42%).

¹H NMR (500 MHz, CDCl₃) δ 7.99-7.95 (m, 2H); 7.91 (s, 1H); 7.56 (d,J=8.92 Hz, 1H); 7.27-7.22 (m, 1H); 6.91-6.81 (m, 2H); 6.68 (d, J=8.93Hz, 1H); 6.50 (brs, 1H); 3.83 (s, 3H); 3.80 (s, 3H); 3.08 (brs, 4H);2.64 (brs, 4H); 2.36 (s, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 159.2, 153.9, 153.1, 144.4, 143.7, 137.3,136.6, 128.4, 123.8, 121.1, 120.9, 118.8, 114.3, 112.3, 106.3, 104.8,55.7, 55.6, 55.5, 51.1, 46.3.

HRMS (APCI): calcd. for C₂₆H₂₉N₄O₃ [M+H]⁺=445.2234; found[M+H]⁺=445.2235.

Preparative Example 9

To a stirred solution of the product from Preparative Example 6C (0.049g; 0.14 mmol) in ethanol (2 mL) was added aqueous solution of HCl (3M;0.9 mL; 2.7 mmol) and the resulting mixture was stirred under N₂ at 60°C. for 8 h. Then, the ethanol and HCl were evaporated and the oilyresidue was mixed with CH₂Cl₂ (2 mL), MeOH (1 mL) and Na₂CO₃ (200 mg)and the mixture was stirred at 25° C. After 20 min., the solvents wereevaporated and the solid residue was purified by column chromatographyon silica gel (eluent:CH₂Cl₂/7N NH₃ in MeOH—10:1) to yield the productas a pale yellow solid (0.026 g; 75%).

¹H NMR (500 MHz, CD₃OD) δ 8.36 (s, 1H); 8.31-8.08 (m, 4H); 7.85 (d,J=8.64 Hz, 1H); 7.63 (d, J=8.64 Hz, 1H); 7.49-7.44 (m, 2H); 7.36-7.31(m, 1H).

¹³C NMR (126 MHz, CD₃OD) δ 150.2, 149.0, 147.1, 146.8, 138.6, 132.2,129.7, 128.6, 128.1, 122.5, 120.3, 117.2.

HRMS (APCI): calcd. for C₁₆H₁₂N₃O [M+H]⁺=262.0975; found[M+H]⁺=262.0976.

Preparative Example 10

The product from Preparative Example 3 (4.5 g; 17.62 mmol) was placedinto a 250 mL round bottom flask. TEA (32 mL) and 1,4-dioxane (32 mL)were added and the mixture was purged with N₂. Ethynyltrimethylsilane(2.25 g; 22.9 mmol), CuI (0.168 g; 0.881 mmol) and PdCl₂(PPh₃)₂ (0.247mg, 0.352 mmol) were added and the mixture was stirred at 45° C. underN₂ for 2.5 h. The solvent was evaporated and the residue was purified bycolumn chromatography (hexane/EtOAc; from 15:1 to 10:1) to yield theproduct as an orange solid (2.90 g; 73% yield).

¹H NMR (500 MHz, CDCl₃) δ 7.67 (dd, J=0.85 Hz, 8.56 Hz, 1H); 7.17 (d,J=8.56 Hz, 1H); 7.03 (d, J=0.84 Hz, 1H); 0.35 (m, 9H).

¹³C NMR (126 MHz, CDCl₃) δ 170.8, 149.9, 148.5, 146.7, 120.7, 119.1,116.8, −1.9.

HRMS (APCI): calcd. for C₁₀H₁₃ClNOSi [M+H]⁺=226.0449; found[M+H]⁺=226.0446.

Preparative Example 11

To a solution of the product from Preparative Example 10 (1.013 g; 4.49mmol) in methanol (20 mL) was added KF (0.803 g; 13.82 mmol) and theresulting mixture was stirred under N₂ at 60° C. for 15 h. Then it wascooled to 25° C., poured into aqueous solution of HCl (0.1M; 100 mL) andextracted with EtOAc (3×60 mL). The organic extracts were dried overNa₂SO₄, filtered, and the solvent was evaporated. The residue waspurified by column chromatography on silica gel(eluent:hexane/EtOAc—10:1) to yield the product as a pale yellow solid(0.579 g; 84%).

¹H NMR (500 MHz, CDCl₃) δ 7.84 (d, J=2.28 Hz, 1H); 7.70 (dd, J=0.84 Hz,8.60 Hz, 1H); 7.21 (d, J=8.60 Hz, 1H); 6.90 (dd, J=0.84 Hz, 2.26 Hz,1H).

¹³C NMR (126 MHz, CDCl₃) δ 150.3, 147.6, 147.2, 146.9, 121.1, 119.5,108.1.

HRMS (APCI): calcd. for C₇H₅ClNO [M+H]⁺=154.0054; found [M+H]⁺=154.0055.

Preparative Example 12A

To a mixture of the product from Preparative Example 11 (0.201 g; 0.89mmol), 1-Boc-pyrazole-4-boronic acid pinacol ester (0.0.317 g; 1.07mmol), K₃PO₄ (0.781 g; 3.68 mmol) and PdCl₂.dppf (0.039 g; 0.053 mmol)were added under N₂ 1,2-dimethoxyethane (4 mL) and water (1 mL). Thereaction mixture was refluxed for 19 h. Then it was cooled to 25° C.,diluted with EtOAc (20 mL), poured into brine (30 mL) and extracted withEtOAc (3×20 mL). The organic extracts were dried over Na₂SO₄, filteredand the solvent was evaporated. The residue was purified by columnchromatography on silica gel (eluent:CH₂Cl₂/MeOH—15:1). So obtainedsolid was further purified by preparative TLC (eluent:CH₂Cl₂/MeOH—15:1)to yield the pale yellow crystalline product (0.080 g; 49%).

¹H NMR (500 MHz, CD₃OD) δ 8.17 (s, 2H); 8.04 (d, J=2.28 Hz, 1H); 7.89(dd, J=0.83 Hz, 8.64 Hz, 1H); 7.62 (d, J=8.65 Hz, 1H); 6.96 (dd, J=0.85Hz, 2.26 Hz, 1H); 4.86 (brs, 1H).

¹³C NMR (126 MHz, CD₃OD) δ 151.4, 150.1, 148.2, 148.1, 133.4, 123.8,120.9, 117.7, 108.2.

HRMS (APCI): calcd. for C₁₀H₈N₃O [M+H]⁺=186.0662; found [M+H]⁺=186.0659.

Preparative Example 12B

To a mixture of the product from Preparative Example 11 (0.052 g; 0.34mmol), 1-methylpyrazole-4-boronic acid pinacol ester (0.092 g; 0.44mmol), K₃PO₄ (0.308 g; 1.45 mmol) and PdCl₂.dppf (0.017 g; 0.023 mmol)were added under N₂ 1,2-dimethoxyethane (2 mL) and water (0.5 mL). Thereaction mixture was refluxed for 14 h. Then it was cooled to 25° C.,diluted with EtOAc (15 mL), poured into brine (25 mL) and extracted withEtOAc (3×15 mL). The organic extracts were dried over Na₂SO₄, filteredand the solvent was evaporated. The residue was purified by columnchromatography on silica gel (eluent:CH₂Cl₂/MeOH—10:1) to yield theproduct as a brown solid (0.045 g; 66%).

¹H NMR (500 MHz, CDCl₃) δ 7.94 (s, 2H); 7.80 (d, J=2.21 Hz, 1H); 7.72(d, J=8.53 Hz, 1H); 7.39 (d, J=8.59 Hz, 1H); 6.95 (d, J=1.64 Hz, 1H);3.94 (s, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 149.3, 149.0, 147.5, 146.7, 137.7, 128.9,124.1, 119.2, 116.0, 108.3, 39.4.

HRMS (APCI): calcd. for C₁₁H₁₀N₃O [M+H]⁺=200.0818; found[M+H]⁺=200.0817.

Preparative Example 13

To a mixture of the product from Preparative Example 10 (1.62 g; 7.16mmol), phenylboronic acid (1.13 g; 9.26 mmol), triethylamine (10 mL;71.8 mmol) and PdCl₂.dppf (0.160 g; 0.22 mmol) were added under N₂1,2-dimethoxyethane (12 mL) and water (3 mL). The reaction mixture wasrefluxed under N₂ for 20 h. Then it was cooled to 25° C., diluted withEtOAc (70 mL), poured into brine (90 mL) and extracted with EtOAc (3×70mL). The organic extracts were dried over Na₂SO₄, filtered and thesolvent was evaporated. The residue was purified by columnchromatography on silica gel (eluent:hexane/EtOAc—15:1) to yield theproduct as a pale yellow solid (1.61 g; 84%).

¹H NMR (500 MHz, CDCl₃) δ 8.01-7.96 (m, 2H); 7.78 (dd, J=0.93 Hz, 8.61Hz, 1H); 7.61 (d, J=8.62 Hz, 1H); 7.49-7.43 (m, 2H); 7.41-7.35 (m, 1H);7.20 (d, J=0.81 Hz, 1H); 0.39-0.39 (m, 9H).

¹³C NMR (126 MHz, CDCl₃) δ 169.5, 154.3, 150.3, 148.6, 140.3, 128.9,128.6, 127.5, 118.7, 117.6, 116.9, −1.8.

HRMS (APCI): calcd. for C₁₆H₁₈NOSi [M+H]⁺=268.1152; found[M+H]⁺=268.1153.

Preparative Example 14

To a stirred solution of the product from Preparative Example 13 (1.61g, 6.02 mmol) in anhydrous CH₂Cl₂ (20 ml) was added MCPBA (1.88 g, 10.9mmol) and the resulting mixture was stirred under N₂ at 25° C. for 72 h.Then it was poured into saturated aqueous solution of NaHCO₃ (110 mL)and extracted with CH₂Cl₂ (3×60 mL). The organic extracts were washedwith brine (50 mL), dried over Na₂SO₄, filtered and the solvent wasevaporated. The residue was purified by column chromatography on silicagel (eluent:CH₂Cl₂/MeOH—12:1) to yield the product as a pale yellowsolid (1.60 g; 94%).

¹H NMR (500 MHz, CDCl₃) δ 7.86-7.80 (m, 2H); 7.50-7.39 (m, 5H); 7.30 (d,J=8.58 Hz, 1H); 0.38-0.36 (m, 9H).

¹³C NMR (126 MHz, CDCl₃) δ 169.0, 153.2, 144.7, 139.6, 133.1, 129.8,129.4, 128.5, 122.2, 112.0, 110.4, −1.9.

HRMS (APCI): calcd. for C₁₆H₁₇NO₂Si [2M+H]⁺=567.213; found[2M+H]⁺=567.2134.

Preparative Example 15

To a stirred solution of the product from Preparative Example 14 (0.575g, 2.03 mmol) in CHCl₃ (10 ml) was added POCl₃ (3.4 mL; 36.5 mmol) andthe resulting mixture was refluxed under N₂ for 1 h. Then, the CHCl₃ andPOCl₃ were evaporated under reduced pressure. The dark oily residue wasdiluted with CH₂Cl₂ (50 mL), poured into saturated aqueous solution ofNaHCO₃ (200 mL) and extracted with CH₂Cl₂ (3×70 mL). The organicextracts were washed with water (50 mL), brine (80 mL), dried overNa₂SO₄, filtered, and the solvent was evaporated. The residue waspurified by column chromatography on silica gel(eluent:hexane/CH₂Cl₂—1:1) to yield the product as a colorless wax(0.339 g; 55%).

¹H NMR (500 MHz, CDCl₃) δ 7.99-7.94 (m, 2H); 7.63 (s, 1H); 7.49-7.44 (m,2H); 7.42-7.37 (m, 1H); 7.20 (s, 1H); 0.41-0.38 (m, 9H).

¹³C NMR (126 MHz, CDCl₃) δ 170.6, 155.4, 149.8, 146.8, 139.3, 129.1,129.0, 127.4, 126.5, 118.1, 117.3, −1.8.

HRMS (APCI): calcd. for C₁₆H₁₆ClNOSi [M+H]⁺=302.0762; found[M+H]⁺=302.0764.

Preparative Example 16

To a solution of the product from Preparative Example 15 (1.11 g; 3.68mmol) in methanol (10 mL) was added KF (0.646 g; 11.1 mmol) and theresulting mixture was stirred under N₂ at 60° C. for 20 h. Then it wascooled to 25° C., poured into aqueous solution of HCl (0.1M; 40 mL) andextracted with EtOAc (3×30 mL). The organic extracts were washed withbrine (30 mL), dried over Na₂SO₄, filtered and the solvent wasevaporated. The residue was purified by column chromatography on silicagel (eluent:CH₂Cl₂/MeOH—20:1) to yield the product as a white solid(0.796 g; 94%).

¹H NMR (500 MHz, CDCl₃) δ 7.99-7.95 (m, 2H); 7.90 (d, J=2.18 Hz, 1H);7.68 (s, 1H); 7.51-7.44 (m, 2H); 7.43-7.39 (m, 1H); 7.09 (d, J=2.15 Hz,1H).

¹³C NMR (126 MHz, CDCl₃) δ 155.8, 150.2, 148.8, 144.0, 138.8, 129.4,129.1, 127.5, 127.0, 117.6, 109.2.

HRMS (APCI): calcd. for C₁₃H₉ClNO [M+H]⁺=230.0367; found[M+H]⁺=230.0365.

Preparative Example 17A

To a solution of the product from Preparative Example 16 (0.103 g; 0.45mmol), (R)-BINAP (0.016 g; 0.026 mmol), Pd(dba)₂ (0.017 g; 0.030 mmol)and t-BuOK (0.078 g; 0.69 mmol) in anhydrous toluene (3 mL) was added3-picolylamine (0.050 mL; 0.49 mmol) and the resulting mixture wasstirred under N₂ at 80° C. for 17 h. Then it was cooled to 25° C.,diluted with EtOAc (10 mL), poured into water (25 mL) and extracted withEtOAc (3×10 mL). The organic extracts were washed with brine (15 mL),dried over MgSO₄, filtered, and the solvent was evaporated. The residuewas purified by column chromatography on silica gel(eluent:CH₂Cl₂/MeOH—10:1) to yield the product as an orange foam (0.056g; 42%).

¹H NMR (500 MHz, CDCl₃) δ 8.62 (d, J=59.05 Hz, 2H); 7.84 (d, J=7.29 Hz,2H); 7.75-7.66 (m, 2H); 7.44-7.25 (m, 4H); 6.96 (d, J=2.02 Hz, 1H); 6.81(s, 1H); 5.09 (brs, 1H); 4.63 (d, J=5.71 Hz, 2H).

¹³C NMR (126 MHz, CDCl₃) δ 156.5, 149.5, 149.3, 147.5, 146.7, 140.8,139.4, 136.8, 135.2, 133.7, 128.8, 128.6, 127.5, 124.0, 109.1, 99.6,45.0.

HRMS (APCI): calcd. for C₁₉H₁₆N₃O [M+H]⁺=302.1288; found[M+H]⁺=302.1285.

Preparative Example 17B

To a solution of the product from Preparative Example 16 (0.207 g; 0.90mmol), (R)-BINAP (0.035 g; 0.056 mmol), Pd(dba)₂ (0.050 g; 0.087 mmol)and t-BuOK (0.146 g; 1.30 mmol) in anhydrous toluene (3 mL) was addedbenzylamine (0.120 mL; 1.10 mmol) and the resulting mixture was stirredunder N₂ at 80° C. for 17 h. Then it was cooled to 25° C., diluted withEtOAc (10 mL), poured into water (25 mL) and extracted with EtOAc (3×10mL). The organic extracts were washed with brine (15 mL), dried overMgSO₄, filtered and the solvent was evaporated. The residue was purifiedby column chromatography on silica gel (eluent:CH₂Cl₂/MeOH—15:1). Soobtained solid was further purified by preparative TLC(eluent:CH₂Cl₂/MeOH—20:1) to yield the product as a brownish foam (0.233g; 86%).

¹H NMR (500 MHz, CDCl₃) δ 7.90-7.85 (m, 2H); 7.69 (d, J=2.19 Hz, 1H);7.44-7.28 (m, 8H); 6.95 (d, J=2.19 Hz, 1H); 6.85 (s, 1H); 4.96 (t,J=5.13 Hz, 1H); 4.59 (d, J=5.63 Hz, 2H).

¹³C NMR (126 MHz, CDCl₃) δ 156.6, 147.2, 146.7, 141.2, 139.7, 138.1,136.9, 129.1, 128.7, 128.4, 128.0, 127.7, 127.6, 109.2, 99.5, 47.4.

HRMS (APCI): calcd. for C₂₀H₁₇N₂O [M+H]⁺=301.1335; found[M+H]⁺=301.1335.

Preparative Example 17C

To a freshly prepared solution of xantphos (0.012 g; 0.021 mmol) andPd₃(dba)₂ (0.022 g; to 0.024 mmol) in anhydrous 1,2-dimethoxyethane (2mL) were added the product from Preparative Example 16 (0.049 g; 0.22mmol), t-BuOK (0.052 g; 0.46 mmol) and 4-morpholinoaniline (0.048 g;0.27 mmol) and the resulting mixture was stirred under N₂ at 100° C. for16 h. Then it was cooled to 25° C., diluted with EtOAc (15 mL), pouredinto brine (25 mL) and extracted with EtOAc (3×15 mL). The organicextracts were dried over MgSO₄, filtered, and the solvent wasevaporated. The residue was purified by column chromatography on silicagel (eluent:CH₂Cl₂/MeOH—15:1). So obtained oil was further purified bypreparative TLC (eluent:CH₂Cl₂/MeOH—20:1) to yield the product as abrownish solid (0.018 g; 22%).

¹H NMR (500 MHz, CDCl₃) δ 7.86-7.83 (m, 2H); 7.74 (d, J=2.20 Hz, 1H);7.42-7.37 (m, 2H); 7.36-7.31 (m, 1H); 7.26-7.21 (m, 2H); 7.15 (s, 1H);6.99 (d, J=2.20 Hz, 1H); 6.97-6.93 (m, 2H); 6.34 (brs, 1H); 3.90-3.85(m, 4H); 3.20-3.14 (m, 4H).

¹³C NMR (126 MHz, CDCl₃) δ 156.3, 149.1, 147.5, 147.2, 140.9, 137.9,137.0 131.4, 128.7, 128.5, 127.6, 1241, 116.9, 109.2, 100.3, 67.1, 49.8.

HRMS (APCI): calcd. for C₂₃H₂₂N₃O₂ [M+H]⁺=372.1707; found[M+H]⁺=372.1707.

Preparative Examples 17D-17I

By essentially same procedure set forth in Preparative Example 17C,using proper amines instead of 4-morpholinoaniline, the compounds givenbelow were prepared.

Preparative Example 17D

Brown semi-solid.

¹H NMR (500 MHz, CDCl₃) δ 7.87-7.83 (m, 2H); 7.74 (d, J=2.21 Hz, 1H);7.42-7.37 (m, 2H); 7.35-7.31 (m, 1H); 7.25 (s, 1H); 6.98 (d, J=2.20 Hz,1H); 6.95 (d, J=8.36 Hz, 1H); 6.87 (dd, J=2.33 Hz, 8.36 Hz, 1H); 6.83(d, J=2.33 Hz, 1H); 6.38 (brs, 1H); 3.84 (s, 3H); 3.20-3.02 (m, 4H);2.69-2.58 (m, 4H); 2.36 (s, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 156.4, 153.3, 147.6, 147.4, 140.9, 138.8,137.4, 137.0, 134.4, 128.7, 128.5, 127.5, 119.2, 115.3, 109.3, 107.1,100.6, 55.9, 55.6, 50.9, 46.3.

HRMS (APCI): calcd. for C₂₅H₂₇N₄O₂ [M+H]⁺=415.2129; found[M+H]⁺=415.2130.

Preparative Example 17E

Orange solid.

¹H NMR (500 MHz, DMSO-d₆) δ 8.36 (d, J=2.26 Hz, 1H); 8.01-7.97 (m, 2H);7.93 (s, 1H); 7.61-7.50 (m, 3H); 7.48-7.43 (m, 1H); 7.38 (s, 1H); 7.21(d, J=2.25 Hz, 1H); 2.33 (s, 3H).

¹³C NMR (126 MHz, DMSO-d₆) δ 168.5, 153.3, 150.6, 146.5, 143.5, 138.8,130.8, 128.7, 128.7, 126.6, 121.5, 110.7, 108.0, 53.7, 20.0.

HRMS (APCI): calcd. for C₁₇H₁₄N₃OS [M+H]⁺=308.0852; found[M+H]⁺=308.0850.

Preparative Example 17F

Pale yellow solid.

¹H NMR (500 MHz, CDCl₃) δ 7.89-7.86 (m, 2H); 7.76 (d, J=2.21 Hz, 1H);7.44-7.29 (m, 8H); 7.18-7.14 (m, 1H); 7.00 (d, J=2.22 Hz, 1H); 6.48(brs, 1H).

¹³C NMR (126 MHz, CDCl₃) δ 156.4, 147.7, 147.6, 140.9, 139.5, 137.2,136.4, 129.9, 128.8, 128.5, 127.5, 124.5, 121.8, 109.3, 101.0.

HRMS (APCI): calcd. for C₁₉H₁₅N₂O [M+H]⁺=287.1179; found[M+H]⁺=287.1178.

Preparative Example 17G

Orange semi-solid.

¹H NMR (500 MHz, CDCl₃) δ 7.95-7.90 (m, 2H); 7.69 (d, J=2.17 Hz, 1H);7.46-7.40 (m, 2H); 7.38-7.33 (m, 1H); 6.94 (d, J=2.17 Hz, 1H); 6.81 (s,1H); 5.36-5.23 (m, 1H); 3.43 (dd, J=5.19 Hz, 11.56 Hz, 2H); 2.69-2.62(m, 2H); 2.30 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 156.4, 147.1, 146.6, 141.3, 140.1, 137.0,128.7, 128.4, 127.6, 109.0, 99.5, 57.8, 45.3, 40.2.

HRMS (APCI): calcd. for C₁₇H₂₀N₃O [M+H]⁺=282.1601; found[M+H]⁺=282.1602.

Preparative Example 17H

Pale yellow solid foam.

¹H NMR (500 MHz, CDCl₃) δ 8.41 (s, 1H); 8.03-7.98 (m, 2H); 7.76 (d,J=2.21 Hz, 1H); 7.46-7.42 (m, 2H); 7.39-7.35 (m, 1H); 7.15 (brs, 1H);7.02 (d, J=2.21 Hz, 1H); 1.57 (s, 9H).

¹³C NMR (126 MHz, CDCl₃) δ 156.5, 152.0, 148.1, 147.3, 140.3, 136.9,131.4, 128.8, 128.8, 127.7, 109.4, 105.5, 82.4, 28.5.

HRMS (APCI): calcd. for C₁₈H₁₉N₂O₃ [M+H]⁺=311.1390; found[M+H]⁺=311.1394.

Preparative Example 17I

Orange wax.

¹H NMR (500 MHz, CDCl₃) δ 7.93-7.89 (m, 2H); 7.73 (d, J=2.22 Hz, 1H);7.47-7.41 (m, 2H), 7.40-7.35 (m, 1H); 6.99 (d, J=1.60 Hz, 1H); 6.92 (s,1H); 3.67-3.60 (m, 8H); 1.48 (s, 9H).

¹³C NMR (126 MHz, CDCl₃) δ 156.3, 154.9, 147.2, 142.3, 138.0, 128.8,128.7, 127.6, 108.9, 102.9, 80.4, 48.1, 28.7.

HRMS (APCI): calcd. for C₂₂H₂₆N₃O₃ [M+H]⁺=380.1969; found[M+H]⁺=380.1970.

Preparative Example 18A

To a stirred solution of the product from Preparative Example 17H (0.031g; 0.10 mmol) in ethanol (2 mL) was added aqueous solution of HCl (3M;0.7 mL; 2.1 mmol) and the resulting mixture was stirred under N₂ at 60°C. for 18 h. Then the ethanol and HCl were evaporated and the oilyresidue was treated with CH₂Cl₂ (2 mL), MeOH (1 mL) and Na₂CO₃ (200 mg)and the mixture was stirred at 25° C. After 20 min., the solvents wereevaporated and the solid residue was purified by preparative TLC(eluent:CH₂Cl₂/7N NH₃ in MeOH—50:1) to yield the product as a whitesolid (0.019 g; 88%).

¹H NMR (500 MHz, CDCl₃) δ 7.92-7.87 (m, 2H); 7.72 (d, J=2.20 Hz, 1H);7.45-7.40 (m, 2H); 7.38-7.33 (m, 1H); 6.95 (d, J=2.20 Hz, 1H); 6.92 (s,1H); 4.49 (brs, 2H).

¹³C NMR (126 MHz, CDCl₃) δ 156.1, 147.8, 147.5, 140.6, 138.5, 137.0,128.8, 128.5, 127.5, 109.0, 103.2.

HRMS (APCI): calcd. for C₁₃H₁₁N₂O [M+H]⁺=211.0866; found[M+H]⁺=211.0866.

Preparative Example 18B

By essentially same procedure set forth in Preparative Example 18A,using the product from Preparative Example 17I, the compound given belowwas prepared.

Pale yellow semi-solid.

¹H NMR (500 MHz, CDCl₃) δ 7.93-7.89 (m, 2H); 7.71 (d, J=2.21 Hz, 1H);7.46-7.40 (m, 2H); 7.38-7.34 (m, 1H); 6.96 (d, J=2.22 Hz, 1H); 6.92 (s,1H); 3.65-3.60 (m, 4H); 3.13-3.04 (m, 4H).

¹³C NMR (126 MHz, CDCl₃) δ 156.4, 148.4, 146.9, 142.7, 141.0, 138.2,128.8, 128.5, 127.6, 108.9, 102.8, 49.2, 46.0.

HRMS (APCI): calcd. for C₁₇H₁₈N₃O [M+H]⁺=280.1444; found[M+H]⁺=280.1443.

Preparative Example 19A

To a freshly prepared solution of(S)-1-[(R_(P))-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine(0.012 g; 0.022 mmol) and Pd(OAc)₂ (0.008 g; 0.037 mmol) in anhydrous1,2-dimethoxyethane (2 mL) were added the product from PreparativeExample 16 (0.049 g; 0.21 mmol), t-BuOK (0.038 g; 0.34 mmol) and4-amino-N,N-dimethyl-benzenesulfonamide (0.051 g; 0.25 mmol) and theresulting mixture was stirred under N₂ at 100° C. for 16 h. Then it wasdiluted with EtOAc (15 mL), poured into brine (25 mL) and extracted withEtOAc (3×15 mL). The organic extracts were dried over MgSO₄, filteredand the solvent was evaporated. The residue was purified by columnchromatography on silica gel (eluent:CH₂Cl₂/MeOH—15:1). So obtained oilwas further purified by preparative TLC (eluent:CH₂Cl₂/MeOH—20:1) toyield the yellow semi solid product (0.036 g; 43%).

¹H NMR (500 MHz, CDCl₃) δ 7.90-7.86 (m, 2H); 7.78-7.71 (m, 3H); 7.49 (s,1H); 7.45-7.32 (m, 5H); 7.03 (brs, 1H); 7.00 (d, J=2.15 Hz, 1H); 2.72(s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 156.4, 148.3, 148.3, 144.5, 140.3, 137.6,134.1, 129.8, 129.2, 128.9, 128.9, 127.5, 118.8, 109.2, 103.2, 38.2.

HRMS (APCI): calcd. for C₂₁H₂₀N₃O₃S [M+H]⁺=394.1220; found[M+H]⁺=394.1217.

Preparative Example 19B

By essentially same procedure set forth in Preparative Example 19A,using cyclohexylamine instead of4-amino-N,N-dimethyl-benzenesulfonamide, the compound given below wasprepared.

Yellow wax.

¹H NMR (500 MHz, CDCl₃) δ 7.92-7.87 (m, 2H); 7.66 (d, J=2.17 Hz, 1H);7.45-7.39 (m, 2H); 7.38-7.32 (m, 1H); 6.96 (d, J=2.17 Hz, 1H); 6.81 (s,1H); 4.70 (brs, 1H); 3.65-3.52 (m, 1H); 2.16-2.05 (m, 2H); 1.84-1.75 (m,2H); 1.71-1.62 (m, 1H); 1.48-1.36 (m, 2H); 1.35-1.19 (m, 4H).

¹³C NMR (126 MHz, CDCl₃) δ 156.0, 147.1, 146.0, 140.8, 139.4, 136.7,128.7, 128.5, 127.6, 108.8, 99.5, 51.5, 33.4, 25.8, 25.0.

HRMS (APCI): calcd. for C₁₉H₂₁N₂O [M+H]⁺=293.1648; found[M+H]⁺=293.1647.

Preparative Example 19C

Degassed 1,2-dimethoxyethane (2.5 mL) was added under N₂ into a 10 mLround bottom flask containing Pd₂(dba)₃ (15.9 mg, 0.017 mmol) and SPhos(7.1 mg, 0.017 mmol). After 5 min, the product from Preparative Example16 (40 mg, 0.17 mmol), 5-methylisoxazol-3-amine (20 mg, 0.212 mmol) andCs₂CO₃ (125 mg, 0.383 mmol) were added. The mixture was stirred at 80°C. under N₂ for 24 h, then the temperature was elevated to 120° C. andthe mixture was stirred for additional 24 h. H₂O (15 mL) was added andthe mixture was extracted with EtOAc (3×25 mL). The organic phase wasdried over Na₂SO₄, filtered, and then the solvent was evaporated. Theresidue was purified by column chromatography (CH₂Cl₂/EtOAc; 2:1) andthen by preparative TLC (CH₂Cl₂/EtOAc; 2:1). The product was obtained asa colorless wax (14 mg, 30% yield).

¹H NMR (300 MHz, CDCl₃) δ 8.21 (s, 1H), 8.03 (d, J=7.9 Hz, 2H), 7.77 (d,J=1.7 Hz, 1H), 7.54-7.34 (m, 3H), 7.09-6.96 (m, 2H), 5.92 (s, 1H), 2.42(s, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 169.4, 159.5, 156.4, 147.6, 146.7, 140.0,136.4, 132.8, 128.5, 128.4, 127.3, 109.0, 104.3, 94.8, 12.4.

HRMS (APCI): calcd. for C₁₇H₁₃N₃O₂ [M+H]⁺=292.1081; found[M+H]⁺=292.1082.

Preparative Example 19D

By essentially same procedure set forth in Preparative Example 19C,using isoxazol-3-amine instead of 5-methylisoxazol-3-amine, the compoundgiven below was prepared.

Colorless wax.

¹H NMR (500 MHz, CDCl₃) δ 8.30 (d, J=1.7 Hz, 1H), 8.28 (s, 1H),8.07-8.01 (m, 2H), 7.78 (d, J=2.2 Hz, 1H), 7.52-7.44 (m, 2H), 7.44-7.37(m, 1H), 7.14 (s, 1H), 7.04 (d, J=2.2 Hz, 1H), 6.28 (d, J=1.7 Hz, 1H).

¹³C NMR (126 MHz, CDCl₃) δ 158.2, 157.6, 155.8, 146.8, 146.1, 139.3,135.6, 131.8, 127.7, 127.7, 126.6, 108.3, 103.7, 97.0.

HRMS (APCI): calcd. for C₁₆H₁₁N₃O₂ [M+H]⁺=278.0924; found[M+H]⁺=278.0926.

Preparative Example 19E

By essentially same procedure set forth in Preparative Example 19C,using pyridin-3-amine instead of 5-methylisoxazol-3-amine, the compoundgiven below was prepared.

Colorless wax.

¹H NMR (300 MHz, CDCl₃) δ 8.65 (s, 1H), 8.42 (d, J=4.2 Hz, 1H),7.93-7.84 (m, 2H), 7.78 (d, J=2.2 Hz, 1H), 7.71-7.62 (m, 1H), 7.46-7.31(m, 5H), 7.02 (d, J=2.2 Hz, 1H), 6.66 (s, 1H).

¹³C NMR (126 MHz, CDCl₃) δ 156.4, 148.0, 147.9, 145.3, 143.5, 140.4,137.1, 136.4, 135.5, 128.7, 128.6, 128.2, 127.4, 124.1, 109.2, 101.1.

HRMS (APCI): calcd. for C₁₈H₁₃N₃O [M+H]⁺=288.1131; found[M+H]⁺=288.1132.

Preparative Example 19E

By essentially same procedure set forth in Preparative Example 19C,using 1-methyl-1H-pyrazol-4-amine instead of 5-methylisoxazol-3-amine,the compound given below was prepared.

Yellow wax.

¹H NMR (500 MHz, CDCl₃) δ 7.89-7.84 (m, 2H), 7.75 (d, J=2.2 Hz, 1H),7.55 (s, 1H), 7.46-7.39 (m, 3H), 7.38-7.34 (m, 1H), 6.99 (d, J=2.2 Hz,1H), 6.98 (s, 1H), 6.00 (s, 1H), 3.94 (s, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 156.4, 147.5, 146.9, 140.8, 138.8, 136.6,136.1, 128.6, 128.4, 127.4, 125.9, 121.4, 109.0, 100.0, 39.7.

HRMS (APCI): calcd. for C₁₇H₁₄N₄O [M+H]⁺=291.1240; found[M+H]⁺=291.1237.

Preparative Example 20

To a mixture of the product from Preparative Example 3 (4.34 g; 17.0mmol) and K₂CO₃ (7.07 g; 51.1 mmol) in N,N-dimethylformamide (30 mL) wasadded under N₂ crotyl bromide (2.6 mL; 25.3 mmol). The resultingreaction mixture was stirred under N₂ at 60° C. for 2 h. Then thesolvent was evaporated and the residue was suspended between H₂O (120mL) and CH₂Cl₂ (90 mL). The water phase was extracted with CH₂Cl₂ (3×100mL). The organic extracts were washed with brine (100 mL), dried overNa₂SO₄, filtered and the solvent was evaporated. The residue waspurified by column chromatography on silica gel(eluent:hexane/EtOAc—1:1). So obtained pale yellow solid was washed withcold pentane (3×25 mL) to yield the white crystalline product (4.24 g;81%).

¹H NMR (500 MHz, CDCl₃) δ 7.19-7.11 (m, 1H); 6.93 (d, J=8.46 Hz, 1H);5.93-5.83 (m, 1H); 5.71-5.61 (m, 1H); 4.52 (d, J=5.49 Hz, 2H); 1.75 (d,J=6.42 Hz, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 154.4, 141.6, 131.7, 124.7, 123.7, 121.3,110.0, 70.8, 18.1.

HRMS (APCI): calcd. for C₉H₁₀ClINO [M+H]⁺=309.9490; found[M+H]⁺=309.9488.

Preparative Example 21

The mixture of the product from Preparative Example 20 (4.24 g; 13.7mmol), K₂CO₃ (4.75 g; 34.4 mmol), HCOONa (0.934 g; 13.7 mmol);tetrabutylammonium chloride (4.21 g; 15.1 mmol) and Pd(OAc)₂ (0.185 g;0.82 mmol) in N,N-dimethylformamide (30 mL) was stirred under N₂ at 80°C. for 3 h. Then the solvent was evaporated and the residue wassuspended between H₂O (180 mL) and CH₂Cl₂ (100 mL). The aqueous phasewas extracted with CH₂Cl₂ (3×100 mL). The organic extracts were washedwith brine (100 mL), dried over Na₂SO₄, filtered and the solvent wasevaporated. The residue was purified by column chromatography on silicagel (eluent:hexane/EtOAc—30:1) to yield the product as a pale yellowsolid (0.774 g; 31%).

¹H NMR (500 MHz, CDCl₃) δ 7.66-7.62 (m, 2H); 7.19 (d, J=8.55 Hz, 1H);2.76 (dq, J=1.23 Hz, 7.51 Hz, 2H); 1.33 (t, J=7.52 Hz, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 147.8, 147.4, 146.6, 146.2, 123.6, 120.9,119.2, 16.0, 13.5.

HRMS (APCI): calcd. for C₉H₉ClNO [M+H]⁺=182.0367; found [M+H]⁺=182.0365.

Preparative Example 22

To a freshly prepared solution of(S)-1-[(R_(P))-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine(0.022 g; 0.039 mmol) and Pd(OAc)₂ (0.009 g; 0.039 mmol) in anhydrous1,2-dimethoxyethane (2 mL) were added the product from PreparativeExample (0.087 g; 0.48 mmol), t-BuONa (0.064 g; 0.66 mmol) andN,N-dimethylethylenediamine (0.063 mL; 0.57 mmol) and the resultingmixture was stirred under N₂ at 100° C. for 15 h. Then it was cooled to25° C., diluted with EtOAc (15 mL), poured into brine (25 mL) andextracted with EtOAc (3×15 mL). The organic extracts were dried overMgSO₄, filtered and the solvent was evaporated. The residue was purifiedby column chromatography on silica gel (eluent:CH₂Cl₂/7N NH₃ inMeOH—15:1) to yield the product as an orange oil (0.081 g; 73%).

¹H NMR (500 MHz, CDCl₃) δ 7.46-7.41 (m, 2H); 6.32 (d, J=8.87 Hz, 1H);5.00-4.89 (m, 1H); 3.42 (dd, J=5.69 Hz, 11.45 Hz, 2H); 2.68 (dq, J=1.14Hz, 7.51 Hz, 2H); 2.58 (t, J=6.06 Hz, 2H); 2.28 (s, 6H); 1.31 (t, J=7.51Hz, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 156.7, 145.3, 143.7, 143.2, 123.0, 120.4,104.5, 58.6, 45.5, 40.2, 16.2, 13.5.

HRMS (APCI): calcd. for C₁₃H₂₀N₃O [M+H]⁺=234.1601; found[M+H]⁺=234.1601.

Preparative Example 23

To a mixture of the product from Preparative Example 21 (0.053 g; 0.29mmol), 1-methylpyrazole-4-boronic acid pinacol ester (0.074 g; 0.36mmol), K₃PO₄ (0.262 g; 1.23 mmol) and PdCl₂.dppf (0.013 g; 0.017 mmol)were added under N₂ 1,2-dimethoxyethane (2 mL) and water (0.5 mL). Thereaction mixture was refluxed for 19 h. Then it was cooled to 25° C.,diluted with EtOAc (15 mL), poured into brine (25 mL) and extracted withEtOAc (3×15 mL). The organic extracts were dried over Na₂SO₄, filteredand the solvent was evaporated. The residue was purified by columnchromatography on silica gel (eluent:CH₂Cl₂/MeOH—10:1) to yield theproduct as a brown semi-solid (0.055 g; 83%).

¹H NMR (500 MHz, CDCl₃) δ 8.04-7.91 (m, 2H); 7.64 (d, J=8.49 Hz, 1H);7.58 (s, 1H); 7.36 (d, J=8.51 Hz, 1H); 3.94 (s, 3H); 2.81 (q, J=7.35 Hz,2H); 1.37 (t, J=7.49 Hz, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 148.1, 147.5, 147.1, 145.1, 137.7, 129.0,124.3, 123.7, 118.9, 115.7, 39.3, 16.2, 13.5.

HRMS (APCI): calcd. for C₁₃H₁₄N₃O [M+H]⁺=228.1131; found[M+H]⁺=228.1133.

Preparative Example 24

To a mixture of the product from Preparative Example 21 (1.43 g; 7.85mmol), phenylboronic acid (1.24 g; 10.2 mmol), K₃PO₄ (6.86 g; 32.3 mmol)and PdCl₂.dppf (0.530 g; 0.72 mmol) were added under N₂1,2-dimethoxyethane (50 mL) and water (10 mL). The reaction mixture wasrefluxed under N₂ for 18 h. Then it was cooled to 25° C., diluted withEtOAc (70 mL), poured into brine (100 mL) and extracted with EtOAc (3×70mL). The organic extracts were dried over Na₂SO₄, filtered and thesolvent was evaporated. The residue was purified by columnchromatography on silica gel (eluent:hexane/EtOAc—15:1) to yield theproduct as a pale yellow solid (1.59 g; 91%).

¹H NMR (500 MHz, CDCl₃) δ 8.04 (d, J=7.51 Hz, 2H); 7.73 (d, J=8.54 Hz,1H); 7.63 (d, J=8.51 Hz, 2H); 7.51-7.43 (m, 2H); 7.42-7.35 (m, 1H); 2.86(q, J=7.48 Hz, 2H); 1.41 (t, J=7.37 Hz, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 153.8, 147.9, 147.7, 145.2, 140.4, 128.9,128.6, 127.4, 124.1, 118.7, 116.6, 16.2, 13.6.

HRMS (APCI): calcd. for C₁₅H₁₄NO [M+H]⁺=224.107; found [M+H]⁺=224.1068.

Preparative Example 25

To a stirred solution of the product from Preparative Example 24 (1.59g, 7.12 mmol) in anhydrous CH₂Cl₂ (20 ml) was added MCPBA (2.22 g, 12.9mmol) and the resulting mixture was stirred under N₂ at 25° C. for 72 h.Then it was poured into saturated aqueous solution of NaHCO₃ (150 mL)and extracted with CH₂Cl₂ (3×80 mL). The organic extracts were washedwith brine (80 mL), dried over Na₂SO₄, filtered, and the solvent wasevaporated. The residue was purified by column chromatography on silicagel (eluent:CH₂Cl₂/EtOAc—5:1) to yield the product as a pale yellowsolid (0.545 g; 32%).

¹H NMR (500 MHz, CDCl₃) δ 7.83-7.76 (m, 2H); 7.50-7.35 (m, 5H); 7.27 (d,J=8.60 Hz, 1H); 3.07 (q, J=7.37 Hz, 2H); 1.34 (t, J=7.41, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 151.0, 145.4, 144.0, 137.7, 133.1, 129.9,129.3, 128.4, 122.2, 110.4, 18.1, 14.9.

HRMS (APCI): calcd. for C₁₅H₁₄NO₂ [M+H]⁺=240.1019; found[M+H]⁺=240.1017.

Preparative Example 26

To a stirred solution of the product from Preparative Example 25 (0.713g, 2.98 mmol) in CHCl₃ (15 ml) was added POCl₃ (6 mL, 64.4 mmol) and theresulting mixture was refluxed under N₂ for 1 hr. Then, the CHCl₃ andPOCl₃ were evaporated under reduced pressure. The dark oily residue wasdiluted with CH₂Cl₂ (50 mL), poured into saturated aqueous solution ofNaHCO₃ (200 mL) and extracted with CH₂Cl₂ (3×50 mL). The organicextracts were washed with water (50 mL), with brine (80 mL), dried overNa₂SO₄, filtered and the solvent was evaporated. The residue waspurified by column chromatography on silica gel(eluent:hexane/CH₂Cl₂—2:1) to yield the product as a white solid (0.282g; 37%).

¹H NMR (500 MHz, CDCl₃) δ 8.07-7.98 (m, 2H); 7.69-7.64 (m, 2H);7.52-7.36 (m, 3H); 2.84 (dd, J=6.89 Hz, 14.36 Hz, 2H); 1.45-1.39 (m,3H).

¹³C NMR (126 MHz, CDCl₃) δ 155.0, 149.1, 145.8, 144.2, 139.3, 129.1,129.0, 127.4, 126.3, 124.8, 117.1, 16.3, 13.5.

HRMS (APCI): calcd. for C₁₅H₁₃ClNO [M+H]⁺=258.0680; found[M+H]⁺=258.0678.

Preparative Example 27A

To a solution of the product from Preparative Example 26 (0.202 g; 0.78mmol), (R)-BINAP (0.032 g; 0.052 mmol), Pd₂(dba)₃ (0.044 g; 0.048 mmol)and t-BuOK (0.146 g; 1.30 mmol) in anhydrous toluene (4 mL) was addedbenzylamine (0.100 mL; 0.92 mmol) and the resulting mixture was stirredunder N₂ at 80° C. for 17 h. Then it was cooled to 25° C., diluted withEtOAc (10 mL), poured into water (25 mL) and extracted with EtOAc (3×10mL). The organic extracts were washed with brine (15 mL), dried overMgSO₄, filtered and the solvent was evaporated. The residue was purifiedby column chromatography on silica gel (eluent:CH₂Cl₂/MeOH—20:1) toyield a brownish solid (0.168 g; 65%).

¹H NMR (500 MHz, CDCl₃) δ 7.94-7.89 (m, 2H); 7.49-7.46 (m, 1H);7.43-7.27 (m, 8H);

6.85 (s, 1H); 4.89 (brs, 1H); 4.58 (d, J=5.67 Hz, 2H); 2.83 (dd, J=1.08Hz, 7.49 Hz, 2H); 1.38 (t, J=7.51 Hz, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 155.7, 146.6, 143.1, 141.4, 139.6, 138.3,137.2, 129.1, 128.7, 128.3, 128.0, 127.7, 127.6, 124.6, 99.3, 47.4,16.4, 13.6.

HRMS (APCI): calcd. for C₂₂H₂₁N₂O [M+H]⁺=329.1648; found[M+H]⁺=329.1650.

Preparative Example 27B

By essentially same procedure set forth in Preparative Example 27A,using N,N-dimethylethylenediamine instead of benzylamine, the compoundgiven below was prepared.

Yellow wax.

¹H NMR (500 MHz, CDCl₃) δ 7.99-7.95 (m, 2H); 7.48-7.46 (m, 1H);7.45-7.40 (m, 2H); 7.37-7.32 (m, 1H); 6.81 (s, 1H); 5.19-5.11 (m, 1H);3.41 (dd, J=5.16 Hz, 11.70 Hz, 2H); 2.82 (qd, J=1.20 Hz, 7.50 Hz, 2H);2.66-2.59 (m, 2H); 2.28 (s, 6H); 1.38 (t, J=7.51 Hz, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 155.6, 146.7, 142.9, 141.6, 139.9, 137.3,128.7, 128.2, 127.6, 124.5, 99.3, 57.9, 45.4, 40.3, 16.4, 13.6.

HRMS (APCI): calcd. for C₁₉H₂₄N₃O [M+H]⁺=310.1914; found[M+H]⁺=310.1915.

Preparative Example 28

To a stirred solution of the product from Preparative Example 27A (0.052g, 0.16 mmol) in hot EtOH (2 ml) were added Pd(OH)₂ (37 mg) and ammoniumformate (0.059 g; 0.94 mmol) and the resulting mixture was refluxedunder N₂ for 42 h. Then it was cooled to 25° C., filtered, and thesolvent was evaporated. The residue was purified by preparative TLC(eluent:CH₂Cl₂/NH₃ in MeOH—50:1) to yield the product as a white solid(0.012 g; 32%).

¹H NMR (500 MHz, CDCl₃) δ 7.96 (d, J=7.43 Hz, 2H); 7.50 (s, 1H);7.46-7.39 (m, 2H); 7.38-7.31 (m, 1H); 6.92 (s, 1H); 4.36 (brs, 2H); 2.82(q, J=7.26 Hz, 2H); 1.38 (t, J=7.45 Hz, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 155.3, 147.7, 143.6, 140.9, 138.1, 137.4,128.7, 128.3, 127.4, 124.5, 103.0, 16.4, 13.6.

HRMS (APCI): calcd. for C₁₅H₁₅N₂O [M+H]⁺=239.1179; found[M+H]⁺=239.1179.

Preparative Example 29

To a freshly prepared solution of xantphos (0.022 g; 0.038 mmol) andPd₃(dba)₂ (0.042 g; 0.046 mmol) in anhydrous 1,2-dimethoxyethane (2 mL)were added the product from Preparative Example 26 (0.104 g; 0.40 mmol),t-BuOK (0.097 g; 0.86 mmol) and aniline (0.048 mL; 0.53 mmol) and theresulting mixture was stirred under N₂ at 100° C. for 16 h. Then it wascooled to 25° C., diluted with EtOAc (15 mL), poured into brine (25 mL)and extracted with EtOAc (3×15 mL). The organic extracts were dried overMgSO₄, filtered and the solvent was evaporated. The residue was purifiedby column chromatography on silica gel (eluent:hexane/EtOAc—15:1) toyield the product as a pale solid (0.064 g; 51%).

¹H NMR (500 MHz, CDCl₃) δ 7.96-7.91 (m, 2H); 7.56-7.53 (m, 1H);7.45-7.27 (m, 8H); 7.17-7.12 (m, 1H); 6.40 (brs, 1H); 2.86 (qd, J=1.15Hz, 7.50 Hz, 2H); 1.41 (t, J=7.51 Hz, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 155.5, 147.7, 143.5, 141.1, 139.8, 137.6,136.1, 129.9, 128.7, 128.4, 127.6, 124.8, 124.2, 121.5, 100.9, 16.4,13.6.

HRMS (APCI): calcd. for C₂₁H₁₉N₂O [M+H]⁺=315.1492; found[M+H]⁺=315.1492.

Preparative Example 30

To a freshly prepared solution of xantphos (0.023 g; 0.039 mmol) andPd₃(dba)₂ (0.036 g; 0.039 mmol) in anhydrous 1,2-dimethoxyethane (2 mL)were added the product from Preparative Example 26 (0.104 g; 0.40 mmol),t-BuOK (0.158 g; 1.40 mmol) and 5-amino-3-methyl-isothiazolehydrochloride (0.115 g; 0.76 mmol) and the resulting mixture was stirredunder N₂ at 100° C. for 22 h. Then it was cooled to 25° C., diluted withEtOAc (15 mL), poured into brine (25 mL) and extracted with EtOAc (3×15mL). The organic extracts were dried over MgSO₄, filtered, and thesolvent was evaporated. The residue was purified by columnchromatography on silica gel (eluent:CH₂Cl₂/MeOH—20:1). So obtained oilwas further purified by preparative TLC (eluent:CH₂Cl₂/MeOH—30:1) toyield the product as a pale orange solid (0.053 g; 39%).

¹H NMR (500 MHz, DMSO-d6) δ 8.15-8.12 (m, 1H); 8.03-7.98 (m, 2H);7.94-7.88 (m, 1H); 7.56-7.50 (m, 3H); 7.47-7.43 (m, 1H); 7.37 (s, 1H);2.77 (qd, J=1.05 Hz, 7.48 Hz, 2H); 2.32 (s, 3H); 1.35 (t, J=7.51 Hz,3H).

¹³C NMR (126 MHz, DMSO-d6) δ 168.4, 152.7, 146.4, 146.0, 143.9, 138.9,130.6, 128.7, 128.6, 126.6, 122.8, 121.5, 110.6, 53.9, 20.0, 15.5, 13.3.

HRMS (APCI): calcd. for C₁₉H₁₈N₃OS [M+H]⁺=336.1165; found[M+H]⁺=336.1164.

Preparative Example 31A

To a freshly prepared solution(S)-1-[(R_(P))-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine(0.011 g; 0.021 mmol) and Pd(OAc)₂(0.006 g; 0.028 mmol) in anhydrous1,2-dimethoxyethane (2 mL) were added the product from PreparativeExample 26 (0.109 g; 0.42 mmol), t-BuONa (0.060 g; 0.62 mmol) and3-picolylamine (0.045 mL; 0.44 mmol) and the resulting mixture wasstirred under N₂ at 100° C. for 17 h. Then it was cooled to 25° C.,diluted with EtOAc (15 mL), poured into brine (25 mL) and extracted withEtOAc (3×15 mL). The organic extracts were dried over MgSO₄, filteredand the solvent was evaporated. The residue was purified by columnchromatography on silica gel (eluent:CH₂Cl₂/MeOH—10:1). So obtained oilwas further purified by preparative TLC (eluent:CH₂Cl₂/NH₃ in MeOH—30:1)to yield the product as a pale yellow solid (0.081 g; 58%).

¹H NMR (500 MHz, CDCl₃) δ 8.67 (s, 1H); 8.55 (d, J=4.20 Hz, 1H);7.92-7.86 (m, 2H); 7.73-7.68 (m, 1H); 7.48 (s, 1H); 7.43-7.37 (m, 2H);7.36-7.31 (m, 1H); 7.29-7.25 (m, 1H); 6.81 (s, 1H); 5.01-4.90 (m, 1H);4.62 (d, J=5.83 Hz, 2H); 2.82 (qd, J=0.84 Hz, 7.45, 2H); 1.38 (t, J=7.51Hz, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 155.7, 149.5, 149.3, 146.9, 143.3, 141.1,139.2, 137.1, 135.2, 133.9, 128.7, 128.4, 127.5, 124.6, 123.9, 99.4,45.0, 16.4, 13.6.

HRMS (APCI): calcd. for C₂₁H₂₀N₃O [M+H]⁺=330.1601; found[M+H]⁺=330.1598.

Preparative Examples 31B-31D

By essentially same procedure set forth in Preparative Example 31A,using proper amines instead of 3-picolylamine, the compounds given belowwere prepared.

Preparative Example 31B

Pale yellow solid.

¹H NMR (500 MHz, CDCl₃) δ 7.97-7.91 (m, 2H); 7.78-7.73 (m, 2H);7.59-7.55 (m, 1H); 7.50 (s, 1H); 7.46-7.32 (m, 5H); 6.90 (brs, 1H); 2.86(qd, J=0.86 Hz, 7.44 Hz, 2H); 2.76-2.70 (m, 6H); 1.40 (t, J=7.51 Hz,3H).

¹³C NMR (126 MHz, CDCl₃) δ 155.3, 148.1, 144.6, 144.3, 140.1, 138.0,133.9, 129.9, 129.3, 128.9, 127.6, 126.6, 124.7, 118.7, 103.1, 38.2,16.4, 13.6.

HRMS (APCI): calcd. for C₂₃H₂₄N₃O₃S [M+H]⁺=422.1533; found[M+H]⁺=422.1534.

Preparative Example 31C

Brown solid.

¹H NMR (500 MHz, CDCl₃) δ 7.92-7.86 (m, 2H); 7.55-7.52 (m, 1H);7.42-7.30 (m, 4H); 7.23-7.20 (m, 1H); 7.17-7.13 (m, 1H); 6.98-6.92 (m,2H); 6.31 (brs, 1H); 3.90-3.84 (m, 4H); 3.20-3.14 (m, 4H); 2.87 (q,J=7.42 Hz, 2H); 1.39 (t, J=7.50 Hz, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 155.3, 149.0, 143.5, 137.3, 131.6, 128.7,128.5, 127.7, 124.6, 124.6, 124.5, 123.8, 117.0, 116.4, 100.3, 67.1,49.8, 16.5, 13.6.

HRMS (APCI): calcd. for C₂₅H₂₆N₃O₂ [M+H]⁺=400.2020; found[M+H]⁺=400.2019.

Preparative Example 31D

Brown solid foam.

¹H NMR (500 MHz, CDCl₃) δ 7.98-7.93 (m, 2H); 7.53-7.50 (m, 1H);7.46-7.40 (m, 2H); 7.39-7.33 (m, 1H); 6.92 (s, 1H); 3.66-3.56 (m, 8H);2.84 (q, J=7.39 Hz, 2H); 1.48 (s, 9H); 1.38 (t, J=7.51 Hz, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 155.4, 154.9, 143.0, 142.2, 138.4, 128.8,128.5, 127.6, 124.2, 102.8, 80.4, 48.1, 28.6, 16.3, 13.6.

HRMS (APCI): calcd. for C₂₄H₃₀N₃O₃ [M+H]⁺=408.2282; found[M+H]⁺=408.2281.

Preparative Example 32

To a stirred solution of the product from Preparative Example 31D (0.088g; 0.22 mmol) in ethanol (2 mL) was added aqueous HCl (3M; 1.4 mL; 4.2mmol) and the resulting mixture was stirred under N₂ at 60° C. for 17 h.Then, the ethanol and HCl were evaporated and the oily residue was mixedwith CH₂Cl₂ (2 mL), MeOH (1 mL) and Na₂CO₃ (200 mg) and the mixture wasstirred at 25° C. After 20 min., the solvents were evaporated and thesolid residue was purified by column chromatography on silica gel(eluent:CH₂Cl₂/7N NH₃ in MeOH—15:1) to yield the product as a pale solid(0.048 g; 72%).

¹H NMR (500 MHz, CDCl₃) δ 7.99-7.94 (m, 2H); 7.51-7.48 (m, 1H);7.46-7.40 (m, 2H); 7.38-7.32 (m, 1H); 6.93 (s, 1H); 3.63-3.56 (m, 4H);3.11-3.04 (m, 4H); 2.82 (qd, J=1.22 Hz, 7.50 Hz, 2H); 2.04 (brs, 1H);1.37 (t, J=7.51 Hz, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 155.4, 148.4, 142.7, 142.6, 141.3, 138.5,128.7, 128.3, 127.5, 124.2, 102.5, 49.3, 46.1, 16.3, 13.6.

HRMS (APCI): calcd. for C₁₉H₂₂N₃O [M+H]⁺=308.1757; found[M+H]⁺=308.1755.

Preparative Example 33

To a mixture of the product from Preparative Example 26 (0.047 g; 0.18mmol), 1-methylpyrazole-4-boronic acid pinacol ester (0.045 g; 0.22mmol), K₃PO₄ (0.163 g; 0.77 mmol) and PdCl₂(dppf) (0.009 g; 0.013 mmol)were added under N₂ 1,2-dimethoxyethane (2 mL) and water (0.5 mL). Thereaction mixture was refluxed for 15 hrs. Then it was cooled to 25° C.,diluted with EtOAc (15 mL), poured into brine (20 mL) and extracted withEtOAc (3×15 mL). The organic extracts were dried over Na₂SO₄, filteredand the solvent was evaporated. The residue was purified by columnchromatography on silica gel (eluent:CH₂Cl₂/EtOAc—10:1). So obtained oilwas further purified by preparative TLC (eluent:CH₂Cl₂) to yield theproduct as a white solid (0.024 g; 43%).

¹H NMR (500 MHz, CDCl₃) δ 8.14 (d, J=3.08 Hz, 2H); 8.07-8.02 (m, 2H);7.73 (s, 1H); 7.67-7.64 (m, 1H); 7.50.7.44 (m, 2H); 7.41-7.36 (m, 1H);3.99 (s, 3H); 2.87 (qd, J=1.10 Hz, 7.49 Hz, 2H); 1.41 (t, J=7.52 Hz,3H).

¹³C NMR (126 MHz, CDCl₃) δ 154.4, 148.2, 144.7, 144.2, 140.4, 138.4,130.5, 128.9, 128.6, 127.5, 124.3, 124.2, 116.1, 112.5, 39.5, 16.3,13.6.

HRMS (APCI): calcd. for C₁₉H₁₈N₃O [M+H]⁺=304.1444; found[M+H]⁺=304.1444.

Preparative Example 34A

Into a 10 mL flask were placed 1,2-dimethoxyethane (3 mL), Pd(OAc)₂ (1.8mg, 0.008 mmol) and CyPF(t-Bu) (4.4 mg, 0.008 mmol) and the mixture wasstirred at 25° C. under N₂ for 5 mm. Then, the product from PreparativeExample 5A (55 mg, 0.20 mmol), N¹,N¹-dimethylpropane-1,3-diamine (24 mg,0.24 mmol) and t-BuONa (28 mg, 0.30 mmol) were added and the mixture wasrefluxed for 22 h. Brine (30 mL) was added and the mixture was extractedwith EtOAc (30+20+20 mL). The organic phase was dried over Na₂SO₄,filtered, and the solvent was evaporated. The residue was purified bypreparative TLC on silica gel (CH₂Cl₂/7M solution of NH₃ in MeOH; 30:1).The product was obtained as a green solid (24 mg, 35%).

¹H NMR (500 MHz, CDCl₃) δ 8.09 (s, 1H), 8.04 (dd, J=8.5, 1.7 Hz, 1H),7.94-7.86 (m, 2H), 7.84 (d, J=7.9 Hz, 1H), 7.56 (d, J=8.9 Hz, 1H),7.52-7.43 (m, 2H), 6.42 (d, J=8.9 Hz, 1H), 3.56 (t, J=6.6 Hz, 2H), 2.53(t, J=6.9 Hz, 2H), 2.31 (s, 6H), 1.94 (p, J=6.8 Hz, 2H).

¹³C NMR (126 MHz, CDCl₃) δ 156.9, 144.02, 143.7, 143.4, 133.8, 132.6,128.9, 128.3, 128.1, 127.7, 126.1, 125.8, 125.7, 124.8, 120.7, 120.6,105.0, 58.0, 45.4, 41.5, 27.0.

HRMS (ESI): calcd. for C₂₂H₂₃N₃O [M+H]⁺=346.1914; found [M+H]⁺=346.1912.

Preparative Example 34B

By essentially same procedure set forth in Preparative Example 34A,using 2-methoxyethanamine instead of N¹,N¹-dimethylpropane-1,3-diamine,the compound given below was prepared.

Dark red solid.

¹H NMR (500 MHz, CDCl₃) δ 8.84 (s, 1H), 8.10 (s, 1H), 8.04 (dd, J=8.5,1.7 Hz, 1H), 7.96-7.87 (m, 2H), 7.87-7.81 (m, 1H), 7.59 (d, J=8.9 Hz,1H), 7.53-7.44 (m, 2H), 6.46 (d, J=8.9 Hz, 1H), 3.72 (s, 4H), 3.43 (s,3H).

¹³C NMR (126 MHz, CDCl₃) δ 156.5, 144.3, 143.9, 133.9, 132.8, 128.8,128.4, 128.2, 127.8, 126.2, 125.9, 125.8, 124.9, 121.0, 120.8, 105.6,71.6, 58.9, 42.4.

HRMS (APCI): calcd. for C₂₀H₁₈N₂O₂ [M+H]⁺=319.1441; found[M+H]⁺=319.1437.

Preparative Example 35

5-bromopyridin-3-ol (1.1 g, 6.3 mmol), iodine (1.6 g, 6.3 mmol), Na₂CO₃(1.4 g, 13.2 g) and H₂O (21 mL) were placed into a 100 mL round bottomflask. The mixture was stirred under N₂ at 25° C. for 3 h. The mixturewas neutralized with 1M aqueous solution of HCl and extracted with EtOAc(60+40+40 mL). The organic phase was washed with brine (50 mL), driedover MgSO₄ and filtered. The product was obtained as a brown solid (1.89g; 100%).

¹H NMR (300 MHz, CDCl₃) δ 8.08 (d, J=2.1 Hz, 1H), 7.38 (d, J=2.1 Hz,1H), 5.39 (s, 1H).

Preparative Example 36

The product from Preparative Example 35 (1.88 g, 6.27 mmol), 1,4-dioxane(12 mL) and TEA (12 mL) were placed into a 100 mL round bottom flask.The mixture was purged with N₂, then ethynyltrimethylsilane (1.15 mL,8.15 mmol), PdCl₂(PPh₃)₂ (132 mg, 0.188 mmol) and CuI (71 mg, 0.376mmol) were added. The mixture was stirred under N₂ at 45° C. for 3 h.The solvent was evaporated and the residue was purified by columnchromatography on silica gel (EtOAc/hexane; 1:15). The product wasobtained as an orange solid (1.04 g, 61%).

¹H NMR (500 MHz, CDCl₃) δ 8.58 (d, J=1.9 Hz, 1H), 7.91 (dd, J=1.9, 1.0Hz, 1H), 7.10 (d, J=1.0 Hz, 1H), 0.37 (s, 9H).

¹³C NMR (126 MHz, CDCl₃) δ 170.2, 150.9, 147.1, 146.8, 121.1, 117.1,115.2, −1.9.

HRMS (APCI): calcd. for C₁₀H₁₂BrNOSi [M+H]⁺=269.9944; found[M+H]⁺=269.9954.

Preparative Example 37

The product from Preparative Example 36 (47 mg, 0.174 mmol),phenylboronic acid (28 mg, 0.226 mmol), 1,2-dimethoxyethane (8 mL), TEA(1 mL) and H₂O (2 mL) were placed into a 25 mL round bottom flask andthe mixture was purged with N₂. Then, PdCl₂(dppf) (3.8 mg, 5.2 μmol) wasadded and the mixture was refluxed under N₂ for 75 mm. After addition ofbrine (25 mL), the mixture was extracted with EtOAc (3×20 mL). Theorganic phase was dried over MgSO₄, filtered, and the solvent wasevaporated. The residue was purified by column chromatography on silicagel (EtOAc/hexane; 1:10). The product was obtained as a white solid (39mg, 84%).

¹H NMR (300 MHz, CDCl₃) δ 8.78 (d, J=1.8 Hz, 1H), 7.93 (d, J=0.7 Hz,1H), 7.69-7.59 (m, 2H), 7.55-7.35 (m, 3H), 7.17 (d, J=0.8 Hz, 1H), 0.40(s, 9H).

¹³C NMR (126 MHz, CDCl₃) δ 169.6, 151.2, 147.5, 145.1, 138.5, 132.9,129.7, 129.2, 127.9, 127.6, 117.1, 116.4, 115.5, −1.8.

HRMS (APCI): calcd. for C₁₆H₁₇NOSi [M+H]⁺=268.1152; found[M+H]⁺=268.1160.

Preparative Example 38

The product from Preparative Example 36 (47 mg, 0.174 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (47mg, 0.226 mmol), 1,2-dimethoxyethane (8 mL), TEA (1 mL) and H₂O (2 mL)were placed into a 25 mL round bottom flask and the mixture was purgedwith N₂. Then, PdCl₂(dppf) (3.8 mg, 5.2 μmol) was added and the mixturewas refluxed under N₂ for 70 min. After addition of brine (25 mL), themixture was extracted with EtOAc (3×20 mL). The organic phase was driedover MgSO₄, filtered, and the solvent was evaporated. The residue waspurified by column chromatography on silica gel (CH₂Cl₂/MeOH; 20:1). Theproduct was obtained as a yellow wax (51 mg, 99%).

¹H NMR (500 MHz, CDCl₃) δ 8.67 (d, J=1.7 Hz, 1H), 7.79 (m, 2H), 7.68 (s,1H), 7.12 (d, J=1.0 Hz, 1H), 3.97 (s, 3H), 0.37 (s, 9H).

¹³C NMR (126 MHz, CDCl₃) δ 168.9, 151.3, 146.7, 143.8, 137.1, 127.3,124.6, 120.5, 117.2, 114.6, 39.3, −1.9.

HRMS (APCI): calcd. for C₁₄H₁₇N₃OSi [M+H]⁺=272.1214; found[M+H]⁺=272.1219.

Preparative Example 39

5-chloropyridin-3-ol (5.12 g, 39.7 mmol), iodine (10.1 g, 39.7 mmol),Na₂CO₃ (8.83 g, 83.3 mmol) and H₂O (80 mL) were placed into a 500 mLround bottom flask and the mixture was stirred under N₂ at 25° C. for3.5 h. The mixture was neutralized with 1M aqueous solution of HCl (ca.120 mL) and extracted with EtOAc (120+70+70 mL). The organic phase waswashed with brine (80 mL), dried over MgSO₄ and filtered. The productwas obtained as a brown solid (10.13 g; 100%).

¹H NMR (300 MHz, DMSO) δ 11.38 (s, 1H), 7.95 (d, J=2.3 Hz, 1H), 7.17 (d,J=2.3 Hz, 1H).

Preparative Example 40

The product from Preparative Example 39 (8.34 g, 32.7 mmol),ethynyltrimethylsilane (6.0 mL, 42.5 mmol), PdCl₂(PPh₃)₂ (688 mg, 0.98mmol), CuI (373 mg, 1.96 mmol), 1,4-dioxane (25 mL) and TEA (25 mL) wereplaced into a 250 mL round bottom flask. The mixture was stirred underN₂ at 45° C. for 2.5 h. The solvent was evaporated and the residue waspurified by column chromatography on silica gel (EtOAc/hexane; 1:15).The product was obtained as an orange solid (4.37 g, 59%).

¹H NMR (500 MHz, CDCl₃) δ 8.52 (dd, J=1.9, 1.4 Hz, 1H), 7.81-7.76 (m,1H), 7.16-7.12 (m, 1H), 0.40 (d, J=1.0 Hz, 9H).

¹³C NMR (126 MHz, CDCl₃) δ 170.3, 150.5, 146.9, 144.9, 127.2, 118.3,117.1, −1.9.

HRMS (APCI): calcd. for C₁₀H₁₂ClNOSi [M+H]⁺=226.0449; found[M+H]⁺=226.0458.

Preparative Example 41

The product from Preparative Example 37 (1.60 g, 5.98 mmol), CH₂Cl₂ (12mL) and mCPBA (1.86 g, 10.8 mmol) were placed into a 100 mL round bottomflask and the mixture was stirred under N₂ at 25° C. for 3 h. Themixture was neutralized with saturated aqueous solution of NaHCO₃ (30mL) and extracted with CH₂Cl₂ (3×25 mL). The organic phase was driedover MgSO₄ and filtered. The solvent was evaporated and the residue waspurified by column chromatography on silica gel (EtOAc/acetone; 9:1).The product was obtained as a white solid (1.38 g, 82%).

¹H NMR (500 MHz, CDCl₃) δ 8.46 (d, J=1.1 Hz, 1H), 7.62 (m, 1H), 7.57 (m,2H), 7.49 (m, 2H), 7.45 (m, 1H), 7.41 (d, J=0.9 Hz, 1H), 0.39 (s, 9H).

¹³C NMR (126 MHz, CDCl₃) δ 169.6, 154.5, 137.7, 136.3, 135.3, 133.4,129.5, 129.0, 127.4, 111.1, 109.3, −2.0.

HRMS (APCI): calcd. for C₁₆H₁₇NO₂Si [M+H]⁺=284.1101; found[M+H]⁺=284.1099.

Preparative Example 42

The product from Preparative Example 41 (1.35 g, 4.75 mmol), chloroform(10 mL) and POCl₃ (7.96 mL, 8.54 mmol) were placed into a 100 mL roundbottom flask and the mixture was refluxed under N₂ for 1 h. The solventand POCl₃ were evaporated and the residue was mixed with saturatedaqueous solution of NaHCO₃ (50 mL) and extracted with CH₂Cl₂ (50+25+25mL). The organic phase was dried over MgSO₄ and filtered. The solventwas evaporated and the residue was purified by column chromatography onsilica gel (EtOAc/CH₂Cl₂; 1:20). The product was obtained as a whitesolid (0.824 g, 57%).

¹H NMR (500 MHz, CDCl₃) δ 8.49 (s, 1H), 7.55-7.42 (m, 5H), 7.20 (s, 1H),0.42 (s, 9H).

¹³C NMR (126 MHz, CDCl₃) δ 170.4, 148.3, 147.9, 147.6, 135.6, 132.0,130.1, 128.5, 128.3, 124.3, 117.7, −1.8.

HRMS (APCI): calcd for C₁₆H₁₆ClNOSi [M+H]⁺=302.0762; found[M+H]⁺=302.0765.

The structural integrity of this compound was also confirmed by X-raycrystallography.

Preparative Example 43

Pd(OAc)₂ (16.7 mg, 74 μmol), SPhos (40 mg, 99 μmol) and 1-butanol (5 mL)were placed into a 25 mL flask and stirred for 5 min. The product fromPreparative Example 42 (750 mg, 2.48 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(724 mg, 3.48 mmol), TEA (10.4 mL, 74 mmol) and H₂O (1 mL) were addedand the mixture was refluxed for 15 h. The solvent was evaporated andthe residue was purified by column chromatography on silica gel(EtOAc/CH₂Cl₂; 1:10). The product was obtained as a pale yellow solid(427 mg, 50%).

¹H NMR (500 MHz, CDCl₃) δ 8.41 (s, 1H), 7.58 (s, 1H), 7.47-7.41 (m, 3H),7.38-7.32 (m, 2H), 7.27 (s, 1H), 7.20 (s, 1H), 3.84 (s, 3H), 0.42 (s,9H).

¹³C NMR (126 MHz, CDCl₃) δ 168.5, 148.0, 147.8, 147.6, 140.9, 139.1,131.4, 130.3, 130.1, 128.9, 128.0, 122.5, 117.5, 114.3, 39.2, −1.7.

HRMS (APCI): calcd. for C₂₀H₂₁N₃OSi [M+H]⁺=348.1527; found[M+H]⁺=348.1529.

Preparative Example 44

The product from Preparative Example 43 (420 mg, 1.21 mmol), CH₂Cl₂ (5mL) and mCPBA (375 mg, 2.18 mmol) were placed into a 25 mL round bottomflask and the mixture was stirred under N₂ at 25° C. for 1 h. Themixture was mixed with saturated aqueous solution of NaHCO₃ (40 mL),brine (30 mL) was added and the mixture was extracted with CH₂Cl₂(50+25+25 mL). The organic phase was dried over MgSO₄ and filtered. Thesolvent was evaporated and the residue was purified by columnchromatography on silica gel (EtOAc/acetone; 2:1). The product wasobtained as a light yellow semi-solid (357 mg, 81%).

¹H NMR (500 MHz, CDCl₃) δ 8.13 (s, 1H), 7.49 (s, 1H), 7.47-7.42 (m, 4H),7.34-7.28 (m, 2H), 7.15 (s, 1H), 3.82 (s, 3H), 0.42 (s, 9H).

¹³C NMR (126 MHz, CDCl₃) δ 168.8, 151.0, 140.1, 137.5, 136.8, 135.5,132.2, 130.6, 129.7, 129.1, 128.8, 116.2, 113.5, 111.4, 39.2, −1.9.

HRMS (APCI): calcd. for C₂₀H₂₁N₃O₂Si [M+H]⁺=364.1476; found[M+H]⁺=364.1478.

Preparative Example 45

The product from Preparative Example 44 (351 mg, 0.966 mmol) and POCl₃(4 mL) were placed into a 25 mL round bottom flask and the mixture wasstirred under N₂ at 100° C. for 25 min. The POCl₃ was evaporated, theresidue was mixed with saturated aqueous solution of NaHCO₃ (25 mL) andextracted with CH₂Cl₂ (20+15+15 mL). The organic phase was dried overMgSO₄ and filtered. The solvent was evaporated and the residue waspurified by column chromatography on silica gel (EtOAc/hexane; 1:1). Theproduct was obtained as a white solid (316 mg, 86%).

¹H NMR (500 MHz, CDCl₃) δ 7.53-7.47 (m, 4H), 7.28-7.26 (m, 1H),7.26-7.25 (m, 1H), 7.13 (s, 1H), 6.96 (s, 1H), 3.78 (s, 3H), 0.42 (s,9H).

¹³C NMR (126 MHz, CDCl₃) δ 169.6, 147.4, 147.3, 146.9, 140.9, 138.5,131.6, 130.3, 129.2, 128.5, 127.8, 126.0, 116.9, 114.5, 39.2, −1.8.

HRMS (APCI): calcd. for C₂₀H₂₀ClN₃OSi [M+H]⁺=382.1137; found[M+H]⁺=382.1141.

Preparative Example 46

The product from Preparative Example 45 (285 mg, 0.746 mmol), KF (130mg, 2.24 mmol) and MeOH (16 mL) were placed into a 50 mL round bottomflask and the mixture was stirred under N₂ at 62° C. for 43 h. Thesolvent was evaporated and the residue was purified by columnchromatography on silica gel (EtOAc/hexane; 1:1). The product wasobtained as a white solid (213 mg, 92%).

¹H NMR (500 MHz, CDCl₃) δ 7.93 (d, J=2.3 Hz, 1H), 7.52-7.47 (m, 3H),7.31-7.26 (m, 3H), 7.21 (s, 1H), 7.00 (d, J=2.3 Hz, 1H), 3.80 (s, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 149.4, 148.0, 146.0, 144.4, 140.7, 138.2,131.9, 130.3, 129.2, 128.6, 128.3, 126.6, 114.0, 108.3, 39.2.

HRMS (APCI): calcd. for C₁₈H₁₂ClN₃O [M+H]⁺=310.0742; found[M+H]⁺=310.0750.

Preparative Example 47

The product from Preparative Example 38 (2.36 g, 8.7 mmol), CH₂Cl₂ (15mL) and mCPBA (2.1 g, 15.7 mmol) were placed into a 100 mL round bottomflask and the mixture was stirred under N₂ at 25° C. for 45 h. Then,additional mCBPA (0.62 g, 3.6 mmol) was added and the mixture wasstirred for additional 4 h. The mixture was mixed with saturated aqueoussolution of NaHCO₃ (20 mL), brine (30 mL) was added, and the mixture wasextracted with CH₂Cl₂ (3×70 mL). The organic phase was dried over MgSO₄and filtered. The solvent was evaporated and the residue was purified bycolumn chromatography on silica gel (EtOAc/MeOH; from 20:1 to 5:1). Theproduct was obtained as a light yellow solid (1.67 g, 66%).

¹H NMR (300 MHz, CDCl₃) δ 8.36 (d, J=0.9 Hz, 1H), 7.76 (s, 1H), 7.63 (s,1H), 7.49 (s, 1H), 7.36 (d, 1H), 3.98 (s, 3H), 0.38 (s, 9H).

¹³C NMR (126 MHz, CDCl₃) δ 168.9, 154.6, 137.1, 131.9, 127.6, 126.8,118.6, 111.1, 107.4, 39.5, −2.0.

HRMS (APCI): calcd. for C₁₄H₁₇N₃O₂Si [2M+H]⁺=575.2253; found[2M+H]⁺=575.2255.

Preparative Example 48

The product from Preparative Example 47 (1.67 g, 5.81 mmol), chloroform(12 mL) and POCl₃ (9.75 mL, 105 mmol) were placed into a 100 mL roundbottom flask and the mixture was refluxed under N₂ for 45 min. Thesolvent and POCl₃ were evaporated and the residue was mixed withsaturated aqueous solution of NaHCO₃ (40 mL) and extracted with CH₂Cl₂(50+30+30 mL). The organic phase was dried over MgSO₄ and filtered. Thesolvent was evaporated and the residue was purified by columnchromatography on silica gel (CH₂Cl₂/MeOH; 14:1). The product wasobtained as a white solid (1.15 g, 65%).

¹H NMR (500 MHz, CDCl₃) δ 8.58 (s, 1H), 7.87 (s, J=0.6 Hz, 1H), 7.83 (s,1H), 7.15 (s, 1H), 4.00 (s, 3H), 0.40 (s, 9H).

¹³C NMR (126 MHz, CDCl₃) δ 169.9, 148.2, 147.3, 146.4, 139.0, 129.8,123.5, 123.2, 117.7, 116.5, 39.3, −1.9.

HRMS (APCI): calcd. for C₁₄H₁₆N₃OSi [M+H]⁺=306.0824; found[M+H]⁺=306.0825.

Preparative Example 49

Pd(OAc)₂ (25 mg, 113 μmol), SPhos (62 mg, 150 μmol) and 1-butanol (8 mL)were placed into a 50 mL flask and stirred for 5 mm. The product fromPreparative Example 48 (1.15 g, 3.76 mmol), phenylboronic acid (688 mg,5.64 mmol), TEA (15.7 mL, 113 mmol) and H₂O (1.6 mL) were added and themixture was refluxed under N₂ for 90 mm. The solvent was evaporated andthe residue was purified by column chromatography on silica gel(EtOAc/MeOH; from 20:1 to 15:1). The product was obtained as a lightgrey solid (1.32 g, 100%).

¹H NMR (500 MHz, CDCl₃) δ 8.64 (s, 1H), 7.45-7.39 (m, 5H), 7.25 (d,J=0.6 Hz, 1H), 7.17 (s, 1H), 7.04 (s, 1H), 3.81 (s, 3H), 0.32 (s, 9H).

¹³C NMR (126 MHz, CDCl₃) δ 169.0, 149.3, 147.1, 146.8, 139.1, 133.5,130.1, 130.1, 129.2, 128.5, 128.5, 122.8, 118.7, 117.3, 39.0, −1.8.

HRMS (APCI): calcd. for C₂₀H₂₁N₃OSi [M+H]⁺=348.1527; found[M+H]⁺=348.1530.

Preparative Example 50

The product from Preparative Example 49 (1.3 g, 3.74 mmol), CH₂Cl₂ (10mL) and mCPBA (1.16 g, 6.73 mmol) were placed into a 50 mL round bottomflask and the mixture was stirred under N₂ at 25° C. for 135 min. Themixture was mixed with saturated aqueous solution of NaHCO₃ (40 mL) andthen extracted with CH₂Cl₂ (50+40+40 mL). The organic phase was driedover MgSO₄ and filtered. The solvent was evaporated and the residue waspurified by column chromatography on silica gel (EtOAc/MeOH; from 10:1to 7:1). The product was obtained as a white semi-solid (1.13 g, 83%).

¹H NMR (500 MHz, CDCl₃) δ 8.33 (s, 1H), 7.47-7.40 (m, 4H), 7.40-7.33 (m,2H), 7.21 (s, 1H), 7.00 (s, 1H), 3.81 (s, 3H), 0.31 (s, 9H).

¹³C NMR (126 MHz, CDCl₃) δ 169.2, 152.6, 138.9, 136.9, 134.2, 132.4,130.2, 129.5, 128.8, 128.7, 125.3, 123.3, 116.9, 111.2, 39.2, −2.0.

HRMS (APCI): calcd. for C₂₀H₂₁N₃O₂Si [M+H]⁺=364.1476; found[M+H]⁺=364.1479.

Preparative Example 51

The product from Preparative Example 50 (1.13 g, 3.11 mmol) and POCl₃ (6mL) were placed into a 50 mL round bottom flask and the mixture wasstirred under N₂ at 100° C. for 20 mm. The POCl₃ was evaporated, theresidue was mixed with saturated aqueous solution of NaHCO₃ (100 mL) andextracted with CH₂Cl₂ (60+40+40 mL). The organic phase was dried overMgSO₄ and filtered. The solvent was evaporated and the residue waspurified by column chromatography on silica gel (EtOAc/hexane; 1:2). Theproduct was obtained as a white solid (1.02 g, 86%).

¹H NMR (300 MHz, CDCl₃) δ 7.38-7.32 (m, 3H), 7.31-7.26 (m, 3H), 7.14 (s,1H), 7.10 (s, 1H), 3.83 (s, 3H), 0.32 (s, 9H).

¹³C NMR (126 MHz, CDCl₃) δ 170.8, 148.5, 147.6, 146.6, 141.0, 134.6,133.4, 131.2, 130.2, 128.5, 128.2, 121.5, 116.7, 116.5, 39.0, −1.9.

HRMS (APCI): calcd. for C₂₀H₂₀ClN₃OSi [M+H]⁺=382.1137; found[M+H]⁺=382.1141.

Preparative Example 52

By essentially same procedure set forth in Preparative Example 46, usingthe product from Preparative Example 51, the compound given below wasprepared.

White solid.

¹H NMR (500 MHz, CDCl₃) δ 7.83 (d, J=2.3 Hz, 1H), 7.38-7.35 (m, 3H),7.29-7.26 (m, 3H), 7.17 (s, 1H), 6.98 (d, J=2.3 Hz, 1H), 3.83 (s, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 150.3, 148.0, 145.6, 140.9, 135.2, 133.0,131.1, 130.0, 128.8, 128.4, 122.2, 116.2, 108.1, 39.1.

HRMS (APCI): calcd. for C₁₇H₁₂ClN₃O [M+H]⁺=310.0742; found[M+H]⁺=310.0746.

Preparative Example 53

The product from Preparative Example 52 (30 mg, 0.969 mmol),1,2-dimethoxyethane (2 mL), K₃PO₄ (61.7 mg, 0.291 mmol),(4-(methoxycarbonyl)phenyl)boronic acid (26.1 mg, 0.145 mmol) andPdCl₂(dppf) (4.3 mg, 5.8 μmol) were placed into a 25 mL round bottomflask. The mixture was refluxed under N₂ for 25 h, then additionalPdCl₂(dppf) (5 mg, 6 μmol) and H₂O (0.4 mL) were added and the mixturewas refluxed for additional 14 h. The solvent was evaporated and theresidue was purified by column chromatography on silica gel(EtOAc/hexane; 1:1). The product was obtained as a colorless wax (17 mg,43%).

¹H NMR (500 MHz, CDCl₃) δ 8.00-7.94 (m, 2H), 7.85 (d, J=1.7 Hz, 1H),7.48-7.43 (m, 2H), 7.39-7.35 (m, 3H), 7.32-7.27 (m, 2H), 7.08 (s, 1H),6.80 (s, 1H), 6.63 (s, 1H), 3.91 (s, 3H), 3.65 (s, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 171.2, 167.1, 155.4, 149.9, 146.5, 146.2,145.8, 140.7, 133.3, 133.1, 130.9, 130.1, 129.9, 129.3, 129.1, 128.5,128.4, 121.9, 117.5, 108.6, 52.2, 38.9.

HRMS (APCI): calcd. for C₂₅H₁₉N₃O₃ [M+H]⁺=410.1499; found[M+H]⁺=410.1492.

Preparative Example 54

The product from Preparative Example 5D (40 mg, 0.14 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(49 mg, 0.168 mmol), K₃PO₄ (104 mg, 0.49 mmol), 1,2-dimethoxyethane (2.4mL), H₂O (0.6 mL) and PdCl₂(dppf) (6.2 mg, 8.4 μmol) were placed into a10 mL round bottom flask and the mixture was refluxed under N₂ for 22 h.Then, additional PdCl₂(dppf) (8 mg, 10.9 μmol) was added and the mixturewas refluxed for additional 4 h. The solvent was evaporated and theresidue was purified by column chromatography on silica gel(EtOAc/hexane; 1:1). The product was obtained as a white solid (18.5 mg,42%).

¹H NMR (500 MHz, DMSO-d6) δ 13.04 (s, 1H), 8.74 (s, 1H), 8.52-8.10 (m,4H), 8.05 (d, J=8.6 Hz, 1H), 7.73 (d, J=8.7 Hz, 1H), 7.54 (d, J=8.2 Hz,2H), 1.35 (s, 9H).

¹³C NMR (126 MHz, DMSO-d6) δ 149.8, 148.8, 146.7, 146.1, 144.8, 128.7,127.7, 126.3, 125.4, 122.4, 119.9, 119.5, 115.9, 34.3, 31.1.

HRMS (APCI): calcd. for C₂₀H₁₉N₃O [M+H]⁺=318.1601; found[M+H]⁺=318.1599.

Preparative Example 55

The product from Preparative Example 5E (11 mg, 52.5 μmol), degassed1,2-dimethoxyethane (2 mL) and H₂O (0.5 mL) were placed into a 5 mLround bottom flask. Then, K₃PO₄ (39 mg, 0.184 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(18.5 mg, 63 μmol) and PdCl₂(dppf) (2 mg, 2.6 μmol) were added and themixture was stirred under N₂ at 60° C. for 16 h. Then, additionalPdCl₂(dppf) (2 mg, 2.6 μmol), the mixture was refluxed for additional 5h, another portion of PdCl₂(dppf) (2 mg, 2.6 μmol) and the mixture wasrefluxed for additional 4 h. The solvent was evaporated and the residuewas purified by column chromatography on silica gel (EtOAc/hexane; 1:1).The product was obtained as a yellow wax (2 mg, 15%).

¹H NMR (500 MHz, CDCl₃) δ 8.24 (b, J=47.6 Hz, 2H), 7.66 (d, J=8.2 Hz,1H), 7.52 (s, 1H), 7.37 (d, J=8.1 Hz, 1H), 1.52 (s, 9H).

¹³C NMR (126 MHz, CDCl₃) δ 8147.7, 143.5, 131.1, 118.7, 115.2, 31.2,29.8.

HRMS (APCI): calcd. for C₁₄H₁₅N₃O [M+H]⁺=242.1288; found[M+H]⁺=242.1292.

Preparative Example 56

The product from Preparative Example 11 (1.78 g, 11.6 mmol) and degassed1,4-dioxane (62 mL) were placed into a 250 mL round bottom flask, thenAcCl (0.825 mL, 11.6 mmol) was added and the mixture was stirred underN₂ at 25° C. After 3 mm, NaI (17.4 g, 116 mmol) was added, the flask waswrapped with aluminum foil and the mixture was stirred at 106° C. for 70h. Additional portions of AcCl were added at these times: 15 h, (0.70mL, 98 mmol); 24 h, (0.80 mL, 11.2 mmol); 40 h (0.80 mL, 11.2 mmol); 48h (0.825 mL, 11.6 mmol; 64 h (0.825 mL, 11.6 mmol). The solvent wasevaporated, the residue was mixed with saturated solution of NaHCO₃ (50mL) and with Na₂S₂O₃ (5 g), and extracted with CH₂Cl₂ (3×90 mL). Theorganic phase was dried over MgSO₄ and filtered. The mixture wasconcentrated to the volume of 75 mL and hexane (25 mL) was added. To thesolution, upon cooling in ice bath, HCl (15 mL, 1M solution in Et₂O) wasadded. The precipitate was collected by filtration. To the solid, TEA(1.9 mL, 14 mmol) and CH₂Cl₂ (20 mL) were added, the mixture was cooledin ice bath, H₂O (60 mL) was added, and the mixture was extracted withCH₂Cl₂ (3×60 mL). The organic phase was dried over MgSO₄, filtered, andthe solvent was evaporated. The product was obtained as a white solid(1.90 g, 67%).

¹H NMR (500 MHz, CDCl₃) δ 7.81 (d, J=2.3 Hz, 1H), 7.60 (d, J=8.5 Hz,1H), 7.47 (dd, J=8.5, 0.9 Hz, 1H), 6.96 (dd, J=2.3, 0.9 Hz, 1H).

¹³C NMR (126 MHz, CDCl₃) δ 149.7, 149.5, 147.5, 129.5, 120.4, 112.0,108.0.

HRMS (APCI): calcd. for C₇H₄INO [M+H]⁺=245.9410; found [M+H]⁺=245.9407.

Preparative Example 57

The product from Preparative Example 56 (1.86 g, 7.60 mmol) and CCl₄ (20mL) were placed into a 100 mL round bottom flask and the mixture wascooled to −18° C. Then, bromine (6.49 mL, 114 mmol) was added slowly.The mixture was stirred under N₂ while allowed to warm up to 25° C. for90 min. The mixture was poured into a mixture of water (100 mL), ice (50mL) and Na₂S₂O₅ (30 g). The resulting mixture was extracted with CH₂Cl₂(2×100 mL) and EtOAc (100 mL). The organic phase was washed with brine(100 mL), dried over MgSO₄, filtered, and the solvent was evaporated.Toluene (24 mL) and DBU (3.4 mL, 22.8 mmol) were added to the residueand the mixture was stirred under N₂ at 80° C. for 45 min. The solventwas evaporated and the residue was and purified by column chromatographyon silica gel (EtOAc/hexane; from 1:7 to 1:5). The product was obtainedas a white solid (1.77 g, 72%).

¹H NMR (500 MHz, CDCl₃) δ 7.85 (s, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.47 (d,J=8.5 Hz, 1H).

¹³C NMR (126 MHz, CDCl₃) δ 147.4, 147.2, 146.8, 131.1, 120.9, 113.0,98.9.

HRMS (APCI): calcd. for C₇H₃BrINO [M+H]⁺=323.8515; found[M+H]⁺=323.8512.

Preparative Example 58

A mixture of the product from Preparative Example 57 (167 mg, 0.515mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(113 mg, 0.54 mmol), K₃PO₄ (383 mg, 1.80 mmol), and PdCl₂(dppf) (18.8mg, 26 μmol) in 1,2-dimethoxyethane (2 mL) and H₂O (0.5 mL) was stirredunder N₂ at 25° C. for 2.5 h. The solvent was evaporated and the residuewas purified by column chromatography on silica gel (hexane/EtOAc; 2:3).The product was obtained as an orange solid (80 mg; 56%).

¹H NMR (500 MHz, CDCl₃) δ 8.04 (s, 1H), 7.97 (s, 1H), 7.85 (s, 1H), 7.73(d, J=8.6 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 3.96 (s, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 149.9, 146.6, 146.3, 144.6, 137.6, 129.3,123.6, 119.6, 116.9, 99.6, 39.3.

HRMS (APCI): calcd. for C₁₁H₈BrN₃O [M+H]⁺=277.9924; found[M+H]⁺=277.9920.

Preparative Example 59

By essentially same procedure set forth in Preparative Example 58, usingtert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylateinstead of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,the compound given below was prepared.

White solid.

¹H NMR (500 MHz, CDCl₃) δ 8.65 (s, 1H), 8.27 (s, 1H), 7.90 (s, 1H), 7.79(d, J=8.6 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H), 1.69 (s, 9H).

¹³C NMR (126 MHz, CDCl₃) δ 148.2, 147.6, 147.1, 146.7, 145.0, 142.5,128.7, 125.7, 119.8, 117.5, 99.7, 86.0, 28.1.

HRMS (APCI): calcd. for C₁₅H₁₄BrN₃O₃ [M+H]⁺=364.0291; found[M+H]⁺=364.0294. The structural integrity of this compound was alsoconfirmed by X-ray crystallography.

Preparative Example 60

A mixture of the product from Preparative Example 57 (127 mg, 0.393mmol), K₃ PO₄ (292 mg, 1.38 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (80.5 mg, 0.413mmol), and PdCl₂(dppf) (14.4 mg, 19.7 μmol) in 1,2-dimethoxyethane (2.8mL) and H₂O (0.7 mL) was stirred under N₂ at 40° C. for 25 h. Thesolvent was evaporated and the residue was purified by columnchromatography on silica gel (CH₂Cl₂/EtOAc; 20:1). The product wasobtained as a white solid (51 mg; 49%).

¹H NMR (500 MHz, CDCl₃) δ 9.00 (s, 1H), 8.88 (s, 1H), 7.93 (s, 1H), 7.82(d, J=8.6 Hz, 1H), 7.50 (d, J=8.6 Hz, 1H).

¹³C NMR (126 MHz, CDCl₃) δ 155.7, 148.4, 147.5, 146.8, 146.1, 145.3,122.2, 119.9, 117.8, 99.7.

HRMS (APCI): calcd. for C₁₀H₅BrN₂O2 [M+H]⁺=264.9607; found[M+H]⁺=264.9603.

Preparative Example 61

Degassed 1-butanol (2.0 mL) and H₂O (0.4 mL) were placed into a 10 mLround bottom flask, Pd(OAc)₂ (1 mg, 4 μmol) and SPhos (2.2 mg, 5.4 μmol)were added and the mixture was stirred at 25° C. for 3 mm. Then, theproduct from Preparative Example 58 (25 mg, 90 μmol),[1,1′-biphenyl]-3-ylboronic acid (25 mg, 0.126 mmol) and TEA (1.0 mL,7.2 mmol) were added. The mixture was stirred under N₂ at 40° C. for 1h, then at 50° C. for 2 h. The solvent was evaporated and the residuepurified by column chromatography on silica gel (hexane/EtOAc; 1:1) andthen by preparative TLC (hexane/acetone; 10:7). The product was obtainedas a white solid (7 mg; 22%).

¹H NMR (500 MHz, CDCl₃) δ 8.57-8.53 (m, 1H), 8.18 (s, 1H), 8.14-8.10 (m,1H), 8.03 (s, 1H), 8.00 (s, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.75-7.71 (m,2H), 7.63-7.54 (m, 2H), 7.53-7.44 (m, 3H), 7.42-7.37 (m, 1H), 3.99 (s,3H).

¹³C NMR (126 MHz, CDCl₃) δ 148.8, 147.6, 145.8, 145.2, 141.7, 141.4,137.7, 131.3, 129.2, 128.9, 128.9, 127.5, 127.3, 126.5, 126.2, 125.9,124.3, 121.4, 119.2, 115.7, 39.3.

HRMS (APCI): calcd. for C₂₃H₁₇N₃O [M+H]⁺=352.1444; found[M+H]⁺=352.1449.

Preparative Example 62

The product from Preparative Example 60 (21 mg, 79.2 μmol), Pd(OAc)₂ (1mg, 4 μmol), SPhos (2 mg, 4.8 μmol), naphthalen-2-ylboronic acid (17.7mg, 103 μmol), 1-butanol (2 mL), H₂O (0.4 mL) and TEA (1.0 mL, 7.17mmol) were placed into a 10 mL round bottom flask. The mixture wasstirred under N₂ at 45° C. for 3 h. The solvent was evaporated, theresidue was purified by column chromatography (hexane/EtOAc; 3:1) andthen by preparative TLC (CH₂Cl₂/EtOAc; 30:1). The product was obtainedas a colorless wax (2.5 mg; 10%).

¹H NMR (500 MHz, CDCl₃) δ 9.02 (s, 1H), 8.94 (s, 1H), 8.87 (s, 1H), 8.30(s, 1H), 8.09 (dd, J=8.5, 1.6 Hz, 1H), 8.00-7.93 (m, 2H), 7.91-7.85 (m,2H), 7.57-7.50 (m, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 155.2, 148.5, 146.5, 146.1, 145.1, 133.8,133.1, 128.5, 128.5, 127.9, 127.7, 126.6, 126.4, 126.3, 124.8, 122.8,121.6, 119.5, 116.9.

HRMS (APCI): calcd. for C₂₀H₁₂N₂O₂ [M+]⁺=313.0972; found[M+H]⁺=313.0975.

Preparative Example 63

By essentially same procedure set forth in Preparative Example 61, using[1,1′-biphenyl]-4-ylboronic acid instead of [1,1′-biphenyl]-3-ylboronicacid, the compound given below was prepared.

White solid.

¹H NMR (500 MHz, CDCl₃) δ 8.28-8.24 (m, 2H), 8.16 (s, 1H), 8.04 (d,J=2.9 Hz, 2H), 7.77 (d, J=8.6 Hz, 1H), 7.76-7.72 (m, 2H), 7.70-7.66 (m,2H), 7.50-7.45 (m, 3H), 7.40-7.35 (m, 1H), 4.00 (s, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 148.8, 147.6, 145.8, 145.1, 141.0, 140.5,137.7, 129.9, 129.0, 128.9, 127.6, 127.5, 127.4, 127.1, 124.3, 121.3,119.2, 115.8, 39.3.

HRMS (APCI): calcd. for C₂₃H₁₇N₃O [M+H]⁺=352.1441; found[M+H]⁺=352.1442.

Preparative Example 64

By essentially same procedure set forth in Preparative Example 61, using[1,1′-biphenyl]-2-ylboronic acid instead of [1,1′-biphenyl]-3-ylboronicacid, the compound given below was prepared.

Colorless wax.

¹H NMR (500 MHz, CDCl₃) δ 8.18 (d, J=7.6 Hz, 1H), 7.98-7.91 (m, 2H),7.67 (d, J=8.6 Hz, 1H), 7.54-7.48 (m, 1H), 7.47-7.42 (m, 2H), 7.38 (d,J=8.6 Hz, 1H), 7.35-7.30 (m, 2H), 7.30-7.22 (m, 3H), 7.17 (s, 1H), 3.97(s, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 148.5, 147.5, 146.6, 146.1, 142.2, 141.6,137.7, 130.9, 130.6, 129.5, 129.1, 128.6, 128.3, 127.8, 127.6, 127.1,124.1, 120.8, 119.0, 115.5, 39.3.

HRMS (APCI): calcd. for C₂₃H₁₇N₃O [M+H]⁺=352.1444; found[M+H]⁺=352.1448.

Preparative Example 65

Degassed 1-BuOH (2.5 mL) and H₂O (0.5 mL) were placed into a 10 mL roundbottom flask, then the product from Preparative Example 58 (40 mg, 144μmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (49.2mg, 0.201 mmol), Pd(PPh₃)₄ (8.3 mg, 7.2 μmol) and K₃PO₄ (92 mg, 0.432mmol) were added. The mixture was stirred under N₂ at 90° C. for 18 h.The solvent was evaporated and the residue was purified by columnchromatography on silica gel (MeOH/EtOAc; 1:10) and then by preparativeTLC (CH₂Cl₂/acetone; 3:2). The product was obtained as a white solid (10mg; 22%).

¹H NMR (500 MHz, acetone-d6) δ 12.35 (b, 1H), 9.06 (d, J=1.0 Hz, 1H),8.66 (s, 1H), 8.27 (s, 1H), 8.14 (s, 1H), 8.06 (d, J=0.9 Hz, 1H), 7.95(d, J=8.7 Hz, 1H), 7.89-7.84 (m, 2H), 7.68 (d, J=8.6 Hz, 1H), 3.98 (s,3H).

¹³C NMR (126 MHz, acetone-d6) δ 150.2, 148.5, 147.3, 146.5, 142.0,138.4, 134.8, 129.9, 129.9, 124.9, 123.6, 122.0, 121.6, 120.5, 120.3,116.8, 109.7, 39.4.

HRMS (APCI): calcd. for C₁₈H₁₂N₅O [M+H]⁺=316.1193; found[M+H]⁺=316.1197.

Preparative Example 66

Degased 1-butanol (2.0 mL) and H₂O (0.4 mL) were placed into a 5 mLround bottom flask. Then, the product from Preparative Example 58 (30mg, 108 μmol), (4-carbamoylphenyl)boronic acid (26.7 mg, 0.162 mmol),Pd(PPh₃)₄ (6.2 mg, 5.4 μmol) and K₃PO₄ (68.6 mg, 0.323 mmol) were added.The mixture was stirred under N₂ at 80° C. for 45 mm. The solvent wasevaporated and the residue was purified by column chromatography onsilica gel (MeOH/EtOAc; 1:10) and then by preparative TLC (MeOH/EtOAc;1:10). The product was obtained as a white solid (12 mg; 35%).

¹H NMR (500 MHz, acetone-d6) δ 8.68 (s, 1H), 8.50-8.45 (m, 2H), 8.28 (s,1H), 8.10-8.05 (m, 3H), 7.95 (d, J=8.7 Hz, 1H), 7.69 (d, J=8.7 Hz, 1H),3.97 (s, 3H).

¹³C NMR (126 MHz, acetone-d6) δ 168.8, 150.5, 148.5, 147.8, 146.2,138.2, 135.1, 134.3, 130.0, 128.9, 127.6, 124.8, 121.3, 120.4, 116.9,39.4.

HRMS (APCI): calcd. for C₁₈H₁₄N₄O₂ [M+H]⁺=319.1190; found[M+H]⁺=319.1187.

Preparative Example 67

By essentially same procedure set forth in Preparative Example 66, using(3-chloro-4-methoxyphenyl)boronic acid instead of(4-carbamoylphenyl)boronic acid, the compound given below was prepared.

White solid.

¹H NMR (500 MHz, acetone-d6) δ 8.56 (s, 1H), 8.43 (d, J=2.1 Hz, 1H),8.34 (dd, J=8.6, 2.2 Hz, 1H), 8.22 (s, 1H), 8.07 (d, J=0.6 Hz, 1H), 7.92(d, J=8.7 Hz, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.25 (d, J=8.6 Hz, 1H), 3.97(d, J=2.0 Hz, 6H).

¹³C NMR (126 MHz, acetone-d6) δ 155.5, 150.2, 148.3, 146.5, 146.2,138.2, 129.8, 129.3, 127.6, 125.6, 124.8, 123.1, 120.4, 120.3, 116.8,113.7, 56.7, 39.4.

HRMS (APCI): calcd. for C₁₈H₁₄ClN₃O₂ [M+H]⁺=340.0847; found[M+H]⁺=340.0842.

Preparative Example 68

Degassed 1-butanol (2.0 mL) and H₂O (0.4 mL) were placed into a 10 mLround bottom flask. Then, the product from Preparative Example 67 (25mg, 0.074 mmol), phenylboronic acid (11.7 mg, 95.7 μmol), Pd(OAc)₂ (1.0mg, 3.7 μmol), SPhos (1.8 mg, 44 μmol) and K₃PO₄ (46.9 mg, 0.220 mmol)were added. The mixture was stirred under N₂ at 80° C. for 4 h. Thesolvent was evaporated and the residue was purified by columnchromatography on silica gel (EtOAc) and then by preparative TLC(CH₂Cl₂/EtOAc; 2:1; 3 runs). The product was obtained as a colorless wax(9 mg; 32%).

¹H NMR (300 MHz, acetone-d6) δ 8.56 (s, 1H), 8.43-8.33 (m, 2H), 8.19 (s,1H), 8.05 (d, J=0.6 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.70-7.61 (m, 3H),7.50-7.33 (m, 3H), 7.24 (d, J=8.5 Hz, 1H), 3.96 (s, 3H), 3.89 (s, 3H).

¹³C NMR (75 MHz, acetone-d6) δ 157.2, 150.0, 148.4, 146.6, 146.2, 139.9,138.2, 131.7, 130.6, 130.4, 129.8, 129.0, 128.3, 127.9, 125.0, 124.8,121.5, 120.1, 116.6, 112.9, 56.2, 39.4.

HRMS (APCI): calcd. for C₂₄H₁₉N₃O₂ [M+H]⁺=382.1550; found[M+H]⁺=382.1547.

Preparative Example 69

By essentially same procedure set forth in Preparative Example 66, using(4-formylphenyl)boronic acid MIDA ester instead of(4-carbamoylphenyl)boronic acid, the compound given below was prepared.

White solid.

¹H NMR (500 MHz, acetone-d6) δ 10.11 (s, 1H), 8.78 (s, 1H), 8.65 (d,J=8.3 Hz, 2H), 8.32 (s, 1H), 8.11 (s, 1H), 8.09-8.04 (m, 2H), 7.99 (d,J=8.7 Hz, 1H), 7.73 (d, J=8.7 Hz, 1H), 3.99 (s, 3H).

¹³C NMR (126 MHz, acetone-d6) δ 192.6, 192.5, 150.7, 148.6, 148.6,146.0, 138.3, 136.7, 130.9, 130.1, 128.2, 124.7, 121.0, 120.5, 117.1,39.4.

HRMS (APCI): calcd. for C₁₈H₁₃N₃O₂ [M+H]⁺=304.1081; found[M+H]⁺=304.1079.

Preparative Example 70

The product from Preparative Example 69 (31 mg, 0.102 mmol), NaBH₄ (8mg, 0.204 mmol) and MeOH (7 mL) were placed into a 10 mL round bottomflask. The mixture was stirred under N₂ at 25° C. for 90 min. Aqueoussaturated solution of NH₄Cl (10 mL) was added and the mixture wasextracted with EtOAc (2×20 mL). The organic phase was washed with brine(10 mL), dried over MgSO₄ and filtered. The solvent was evaporated andthe residue was purified by column chromatography on silica gel(MeOH/EtOAc; 1:12). The product was obtained as a white solid (26 mg;84%).

¹H NMR (500 MHz, acetone-d6) δ 8.54 (s, 1H), 8.33-8.29 (m, 2H), 8.25 (s,1H), 8.06 (d, J=0.6 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.66 (d, J=8.7 Hz,1H), 7.52-7.47 (m, 2H), 4.72-4.68 (m, 2H), 3.96 (s, 3H).

¹³C NMR (126 MHz, acetone-d6) δ 150.2, 148.4, 146.7, 146.5, 142.9,138.2, 130.6, 129.9, 127.8, 127.8, 124.9, 122.0, 120.2, 116.7, 64.7,39.4.

HRMS (APCI): calcd. for C₁₈H₁₅N₃O₂ [M+H]⁺=306.1237; found[M+H]⁺=306.1242.

Preparative Example 71

By essentially same procedure set forth in Preparative Example 66, using(4-(methylsulfonyl)phenyl)boronic acid instead of(4-carbamoylphenyl)boronic acid, the compound given below was prepared.

White solid.

¹H NMR (300 MHz, acetone-d6) δ 8.78 (s, 1H), 8.70-8.63 (m, 2H), 8.31 (s,1H), 8.12-8.02 (m, 3H), 7.98 (d, J=8.7 Hz, 1H), 7.71 (d, J=8.7 Hz, 1H),3.97 (s, 3H), 3.17 (s, 3H).

¹³C NMR (75 MHz, acetone-d6) δ 150.7, 148.7, 148.5, 145.9, 141.0, 138.2,137.4, 130.1, 128.7, 128.3, 124.6, 120.6, 120.4, 117.1, 44.6, 39.4.

HRMS (APCI): calcd. for C₁₈H₁₅N₃O₃S [M+H]⁺=354.0907; found[M+H]⁺=354.0901.

Preparative Example 72

By essentially same procedure set forth in Preparative Example 66, using(4-(methylthio)phenyl)boronic acid instead of (4-carbamoylphenyl)boronicacid, the compound given below was prepared.

White solid.

¹H NMR (500 MHz, acetone-d6) δ 8.55 (s, 1H), 8.35-8.29 (m, 2H), 8.24 (s,1H), 8.06 (d, J=0.5 Hz, 1H), 7.91 (d, J=8.7 Hz, 1H), 7.65 (d, J=8.6 Hz,1H), 7.43-7.38 (m, 2H), 3.96 (s, 3H), 2.55 (s, 3H).

¹³C NMR (126 MHz, acetone-d6) δ 150.2, 148.4, 146.7, 146.4, 139.0,138.2, 129.9, 128.8, 128.3, 127.5, 124.9, 121.5, 120.2, 116.7, 39.4,15.7.

HRMS (ACPI): calcd. for C₁₈H₂₅N₃OS [M+H]⁺=322.1009; found[M+H]⁺=322.1003.

Preparative Example 73

The product from Preparative Example 72 (13 mg, 40.4 μmol) and CH₂Cl₂ (2mL) were placed into a 5 mL round bottom flask. The mixture was cooledto 0° C., then mCPBA (7.0 mg, 40.4 mmol) was added and the mixture wasstirred under N₂ at 0° C. for 45 min. Aqueous saturated solution ofNaHCO₃ (5 mL) and H₂O (5 mL) were added and the mixture was extractedwith CH₂Cl₂ (2×10 mL). The organic phase was dried over MgSO₄ andfiltered. The solvent was evaporated and the residue was purified bypreparative TLC on silica gel (EtOAc/MeOH; 20:1). The product wasobtained as a yellow wax (5 mg; 38%).

¹H NMR (300 MHz, acetone-d6) δ 8.70 (s, 1H), 8.63-8.55 (m, 2H), 8.29 (s,1H), 8.09 (s, 1H), 7.96 (d, J=8.7 Hz, 1H), 7.81 (d, J=8.6 Hz, 2H), 7.69(d, J=8.7 Hz, 1H), 3.97 (s, 3H), 2.76 (s, 3H).

¹³C NMR (75 MHz, acetone-d6) δ 150.4, 148.4, 147.8, 147.1, 146.1, 138.2,134.6, 130.0, 128.4, 124.8, 124.7, 120.9, 120.4, 116.9, 44.4, 39.3.

HRMS (APCI): calcd. for C₁₈H₁₅N₃O₃S [M+H]⁺=338.0958; found[M+H]⁺=338.0955.

Preparative Example 74

By essentially same procedure set forth in Preparative Example 66, using(3-(tert-butyl)phenyl)boronic acid instead of (4-carbamoylphenyl)boronicacid, the compound given below was prepared.

Colorless wax.

¹H NMR (500 MHz, CDCl₃) δ 8.41 (d, J=0.9 Hz, 1H), 8.12 (s, 1H), 8.04 (s,1H), 7.97 (s, 1H), 7.84 (m, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.42 (m, 3H),3.97 (s, 3H), 1.44 (s, 9H).

¹³C NMR (126 MHz, CDCl₃) δ 151.7, 148.6, 147.6, 145.9, 145.0, 137.7,130.4, 128.8, 128.5, 124.8, 124.7, 124.4, 124.1, 122.0, 119.1, 115.6,35.0, 31.6, 31.0.

HRMS (APCI): calcd. for C₂₁H₂₁N₃O [M+H]⁺=332.1757; found[M+H]⁺=332.1754.

Preparative Example 75

6-chloro-5-methylpyridin-3-ol (2.51 g, 17.5 mmol), iodine (4.44 g, 17.5mmol), H₂O (35 mL), THF (30 mL) and Na₂CO₃ (3.90 g, 36.8 mmol) wereplaced into a 100 mL round bottom flask. The mixture was stirred underN₂ at 25° C. for 18 h. The solvent was evaporated and the solution wasneutralized with 1M aqueous solution of HCl (38 mL). Then, saturatedaqueous solution of NH₄Cl (30 mL) and H₂O (100 mL) were added and themixture was extracted with CH₂Cl₂ (80 mL) and EtOAc (2×80 mL). Theorganic phase was washed with brine (30 mL), dried over MgSO₄, filtered,and the solvent was evaporated. The product was obtained as a whitesolid (4.24 g; 90%).

¹H NMR (500 MHz, CDCl₃) δ 7.12 (d, J=0.7 Hz, 1H), 2.31 (d, J=0.7 Hz,3H).

¹³C NMR (126 MHz, CDCl₃) δ 124.8, 19.3.

HRMS (APCI): calcd. for C₆H₅ClINO [M+H]⁺=269.9178; found[M+H]⁺=269.9179.

Preparative Example 76

The product from Preparative Example 75 (2.2 g, 8.16 mmol), degassed1,4-dioxane (17 mL) and TEA (17 mL) were placed into a 100 mL roundbottom flask. Then, ethynyltrimethylsilane (1.49 mL, 10.6 mmol), CuI (78mg, 0.408 mmol) and PdCl₂(PPh₃)₂ (114 mg, 0.163 mmol) were added. Themixture was stirred under N₂ at 45° C. for 3 h. The solvent wasevaporated and the residue was purified by column chromatography onsilica gel (hexane/EtOAc; 10:1). The product was obtained as an orangesolid (930 mg, 47%).

¹H NMR (500 MHz, CDCl₃) δ 7.62 (s, 1H), 7.01 (d, J=0.8 Hz, 1H), 2.48 (s,3H), 0.36 (s, 9H).

¹³C NMR (126 MHz, CDCl₃) δ 169.5, 150.4, 147.1, 146.1, 127.3, 121.1,116.5, 20.6, −1.9.

HRMS (APCI): calcd. for C₁₁H₁₄ClNOSi [M+H]⁺=240.0606; found[M+H]⁺=240.0604.

Preparative Example 77

The product from Preparative Example 76 (0.90 g, 3.75 mmol), MeOH (28mL) and KF (654 mg, 11.3 mmol) were placed into a 100 mL round bottomflask. The mixture was stirred under N₂ at 25° C. for 14 h, then at 60°C. for additional 8 h. The solvent was evaporated and the residue waspurified by column chromatography on silica gel (hexane/EtOAc; from 10:1to 5:1). The product was obtained as a white solid (560 mg, 88%).

¹H NMR (500 MHz, CDCl₃) δ 7.79 (d, J=2.0 Hz, 1H), 7.65 (s, 1H), 6.89 (m,1H), 2.49 (s, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 149.3, 147.6, 147.4, 145.3, 127.8, 121.4,107.7, 20.6.

HRMS (APCI): calcd. for C₈H₆ClNO [M+H]⁺=168.0211; found [M+H]⁺=168.0209.

Preparative Example 78

Degassed 1,2-dimethoxyethane (4.0 mL) and H₂O (1.0 mL) were placed intoa 25 mL round bottom flask. Then, the product from Preparative Example77 (160 mg, 0.94 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(294 mg, 1.42 mmol), PdCl₂(dppf) (34 mg, 47 μmol) and K₃PO₄ (599 mg,2.82 mmol) were added. The mixture was stirred under N₂ at 80° C. for 5h. The solvent was evaporated and the residue was purified by columnchromatography on silica gel (EtOAc/MeOH; from 1:0 to 10:1) and then byanother column chromatography (EtOAc). The product was obtained as awhite solid (120 mg; 60%).

¹H NMR (500 MHz, CDCl₃) δ 7.90 (s, 1H), 7.82 (s, 1H), 7.76 (d, J=2.3 Hz,1H), 7.60 (s, 1H), 6.92 (dd, J=2.2, 0.9 Hz, 1H), 3.97 (s, 3H), 2.56 (s,3H).

¹³C NMR (126 MHz, CDCl₃) δ 148.6, 146.9, 145.3, 139.3, 137.0, 130.3,126.6, 123.2, 120.4, 108.0, 39.1, 21.6.

HRMS (APCI): calcd. for C₁₂H₁₁N₃O [M+H]⁺=214.0975; found[M+H]⁺=214.0972.

Preparative Example 79

The product from Preparative Example 78 (115 mg, 0.54 mmol) and CCl₄ (5mL) were placed into a 100 mL round bottom flask. The mixture was cooledto −18° C., then bromine (0.56 mL, 10.8 mmol) was added slowly. Themixture was allowed to warm to 12° C. and stirred under N₂ for 60 mm.The mixture was poured into a mixture of water (30 mL), ice (20 mL) andNa₂S₂O₅ (2 g). The resulting mixture was extracted with CH₂Cl₂ (20 mL)and EtOAc (2×15 mL). The organic phase was dried over MgSO₄, filtered,and the solvent was evaporated. Toluene (12 mL) and DBU (0.241 mL, 1.62mmol) were added to the residue and the mixture was stirred under N₂ at80° C. for 45 min. The solvent was evaporated and the residue waspurified by column chromatography on silica gel (EtOAc/hexane; 1:1) andthen by preparative TLC (EtOAc/hexane; 2:1). The product was obtained asa white solid (19 mg, 12%).

¹H NMR (500 MHz, CDCl₃) δ 7.93 (d, J=2.3 Hz, 2H), 7.80 (s, 1H), 7.61 (s,1H), 3.98 (s, 3H), 2.60 (s, 3H).

¹³C NMR (126 MHz, CDCl₃) δ 149.2, 146.5, 146.1, 142.5, 139.3, 130.9,127.9, 122.98 (s), 121.0, 99.5, 39.2, 21.7.

HRMS (APCI): calcd. for C₁₂H₁₀BrN₃O [M+H]⁺=292.0080; found[M+H]⁺=292.0075.

Preparative Example 80

Degassed 1-butanol (2.0 mL) and H₂O (0.4 mL) were placed into a 10 mLround bottom flask. Then, the product from Preparative Example 79 (15mg, 51.3 μmol), naphthalen-2-ylboronic acid (13.3 mg, 77 μmol),Pd(PPh₃)₄ (3.0 mg, 2.6 μmol) and K₃PO₄ (32.7 mg, 0.154 mmol) were added.The mixture was stirred under N₂ at 80° C. for 70 mm. The solvent wasevaporated and the residue was purified by column chromatography onsilica gel (EtOAc/CH₂Cl₂; 1:2) and then by preparative TLC(EtOAc/CH₂Cl₂; 2:3). The product was obtained as a colorless wax (8.5mg; 49% yield).

¹H NMR (300 MHz, CDCl₃) δ 8.88 (s, 1H), 8.18 (s, 1H), 8.14-8.07 (m, 2H),7.97-7.84 (m, 4H), 7.64 (d, J=0.5 Hz, 1H), 7.55-7.44 (m, 2H), 4.03 (s,3H), 2.64 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 148.1, 148.0, 144.9, 143.9, 139.8, 133.9,133.0, 130.5, 128.6, 128.5, 128.4, 127.9, 126.5, 126.4, 126.3, 126.1,125.0, 123.9, 121.4, 120.7, 39.3, 21.9.

HRMS (APCI): calcd. for C₂₂H₁₇N₃O [M+H]⁺=340.1444; found[M+H]⁺=340.1440.

Preparative Example 81

Degassed 1-butanol (2.0 mL) and H₂O (0.4 mL) were placed into a 10 mLround bottom flask. Then, the product from Preparative Example 58 (23.8mg, 85.6 μmol), (4-(1H-tetrazol-5-yl)phenyl)boronic acid (19.5 mg, 0.103mmol), Pd(PPh₃)₄ (5.0 mg, 4.3 μmol) and K₃PO₄ (54.5 mg, 0.257 mmol) wereadded. The mixture was refluxed under N₂ for 150 min. The solvent wasevaporated and the residue purified by column chromatography on silicagel (EtOAc/MeOH; from 3:1 to 2:1) and then by preparative TLC (THF/MeOH;2:1). The product was obtained as a colorless semi-solid (12 mg; 41%).

¹H NMR (300 MHz, CD₃OD) δ 8.44 (s, 1H), 8.37-8.30 (m, 2H), 8.20-8.13 (m,3H), 8.05 (d, J=0.7 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.57 (d, J=8.7 Hz,1H), 3.96 (s, 3H).

¹³C NMR (75 MHz, CD₃OD) δ 149.9, 148.9, 147.3, 146.6, 138.4, 132.7,130.7, 130.0, 128.2, 127.9, 126.5, 125.4, 122.0, 120.3, 116.9, 39.1.

HRMS (APCI): calcd. for C₁₈H₁₃N₇O [M+H]⁺=344.1254; found[M+H]⁺=344.1252.

ASSAYS

In vitro essays were performed by the company Merck Millipore in theirKinaseProfiler radiometric protein kinase assay as paid commercialservice. The compounds IC₅₀ values for inhibition of individual proteinkinases were determined. Dose-response curves were plotted frominhibition data generated, each in duplicate, from 10 point serialdilutions of inhibitory compounds. Concentration of compound was plottedagainst % kinase activity. To generate IC₅₀ values, the dose-responsecurves were fitted to a standard sigmoidal curve and IC₅₀ values werederived by standard nonlinear regression analysis.

All tested compounds were prepared in 100% DMSO to final assayconcentrations either 0.5 mM (for the concentration row A, see below) or0.05 mM (for the concentration row B). This working stock of thecompound was added to the assay well as the first component in thereaction, followed by the remaining components as detailed below. Thestock solution was added to the individual assay wells in such amountsthat the concentrations of the compound were either in the row A (0.001μM, 0.003 μM, 0.01 μM, 0.03 μM, 0.1 μM, 0.3 μM, 1.0 μM, 3.0 μM, and 10.0μM) or in the row B (0.0001 μM, 0.0003 μM, 0.001 μM, 0.003 μM, 0.01 μM,0.03 μM, 0.1 μM, 0.3 μM, and 1.0 μM). There was no pre-incubation stepbetween the compound and the kinase prior to initiation of the reaction.

The positive control wells contained all components of the reaction,except the compound of interest; however, DMSO (at a final concentrationof 2%) was included in these wells to control for solvent effects. Theblank wells contained all components of the reaction, with staurosporineas a reference inhibitor replacing the compound of interest. Thisabolished kinase activity and established the base-line (0% kinaseactivity remaining).

CLK2 Assay

CLK2 (h) was diluted in the buffer (20 mM MOPS(3-(N-morpholino)propanesulfonic acid), 1 mM EDTA(ethylendiaminotetraacetic acid), 0.01% Brij-35 (detergent), 5%Glycerol, 0.1% β-mercaptoethanol, 1 mg/mL BSAs) to the concentration of1.01 mg/mL prior to addition to the reaction mix.

The above stock solution of CLK2(h) was added to a mixture containing 8mM MOPS pH 7.0, 0.2 mM EDTA, and 20 μM YRRAAVPPSPSLSRHSSPHQS(p) EDEEE insuch amount that the resulting concentration of CLK2(h) was 2.1 nM. Thismixture was added to the stock solution of the tested compound. Thereaction was initiated by the addition of the MgATP mix in such amountthat the resulting concentration of Mg acetate in the reaction mixturewas 10 mM and [γ-³³P-ATP] (specific activity approx. 500 cpm/pmol) was15 μM. After incubation for 40 minutes at room temperature, the reactionwas stopped by the addition of 3% phosphoric acid solution. 10 μL of thereaction was then spotted onto a P30 filtermat and washed three timesfor 5 minutes in 75 mM phosphoric acid and once in methanol prior todrying and scintillation counting.

CLK4 Assay

CLK4 (h) was diluted in the buffer (20 mM MOPS, 1 mM EDTA, 0.01%Brij-35, 5% Glycerol, 0.1% β-mercaptoethanol, 1 mg/mL BSAs) to theconcentration of 1.01 mg/mL prior to addition to the reaction mix.

The above stock solution of CLK4(h) was added to a mixture containing 8mM MOPS pH 7.0, 0.2 mM EDTA, and 200 μM YRRAAVPPSPSLSRHSSPHQS(p) EDEEEin such amount that the resulting concentration of CLK4(h) was 140.8 nM.This mixture was added to the stock solution of the tested compound. Thereaction was initiated by the addition of the MgATP mix in such amountthat the resulting concentration of Mg acetate in the reaction mixturewas 10 mM and [γ-³³P-ATP] (specific activity approx. 500 cpm/pmol) was15 μM. After incubation for 40 minutes at room temperature, the reactionwas stopped by the addition of 3% phosphoric acid solution. 10 μL of thereaction was then spotted onto a P30 filtermat and washed three timesfor 5 minutes in 75 mM phosphoric acid and once in methanol prior todrying and scintillation counting.

HIPK1 Assay

HIPK1(h) was diluted in the buffer (20 mM MOPS, 1 mM EDTA, 0.01%Brij-35, 5% Glycerol, 0.1% β-mercaptoethanol, 1 mg/mL BSAs) to theconcentration of 1.01 mg/mL prior to addition to the reaction mix.

The above stock solution of HIPK1(h) was added to a mixture containing 8mM MOPS pH 7.0, 0.2 mM EDTA, and 0.33 mg/mL myelin basic protein in suchamount that the resulting concentration of HIPK1(h) was 4.7 nM. Thismixture was added to the stock solution of the tested compound. Thereaction was initiated by the addition of the MgATP mix in such amountthat the resulting concentration of Mg acetate in the reaction mixturewas 10 mM and [γ-³³P-ATP] (specific activity approx. 500 cpm/pmol) was45 μM. After incubation for 40 minutes at room temperature, the reactionwas stopped by the addition of 3% phosphoric acid solution. 10 μL of thereaction was then spotted onto a P30 filtermat and washed three timesfor 5 minutes in 75 mM phosphoric acid and once in methanol prior todrying and scintillation counting.

HIPK2 Assay

HIPK2(h) was diluted in the buffer (20 mM MOPS, 1 mM EDTA, 0.01%Brij-35, 5% Glycerol, 0.1% β-mercaptoethanol, 1 mg/mL BSAs) to theconcentration of 1.01 mg/mL prior to addition to the reaction mix.

The above stock solution of HIPK2(h) was added to a mixture containing 8mM MOPS pH 7.0, 0.2 mM EDTA, and 0.33 mg/mL myelin basic protein in suchamount that the resulting concentration of HIPK2(h) was 1.4 nM. Thismixture was added to the stock solution of the tested compound. Thereaction was initiated by the addition of the MgATP mix in such amountthat the resulting concentration of Mg acetate in the reaction mixturewas 10 mM and [γ-³³P-ATP] (specific activity approx. 500 cpm/pmol) was10 μM. After incubation for 40 minutes at room temperature, the reactionwas stopped by the addition of 3% phosphoric acid solution. 10 μL of thereaction was then spotted onto a P30 filtermat and washed three timesfor 5 minutes in 75 mM phosphoric acid and once in methanol prior todrying and scintillation counting.

HIPK3 Assay

HIPK3(h) was diluted in the buffer (20 mM MOPS, 1 mM EDTA, 0.01%Brij-35, 5% Glycerol, 0.1% β-mercaptoethanol, 1 mg/mL BSAs) to theconcentration of 1.01 mg/mL prior to addition to the reaction mix.

The above stock solution of HIPK3(h) was added to a mixture containing 8mM MOPS pH 7.0, 0.2 mM EDTA, and 1.0 mg/mL myelin basic protein in suchamount that the resulting concentration of HIPK3(h) was 6.4 nM. Thismixture was added to the stock solution of the tested compound. Thereaction was initiated by the addition of the MgATP mix in such amountthat the resulting concentration of Mg acetate in the reaction mixturewas 10 mM and [γ-³³P-ATP] (specific activity approx. 500 cpm/pmol) was15 μM. After incubation for 40 minutes at room temperature, the reactionwas stopped by the addition of 3% phosphoric acid solution. 10 μL of thereaction was then spotted onto a P30 filtermat and washed three timesfor 5 minutes in 75 mM phosphoric acid and once in methanol prior todrying and scintillation counting.

FLT3 Assay

FLT3(h) was diluted in the buffer (20 mM MOPS, 1 mM EDTA, 0.01% Brij-35,5% Glycerol, 0.1% β-mercaptoethanol, 1 mg/mL BSAs) to the concentrationof 1.01 mg/mL prior to addition to the reaction mix.

The above stock solution of Flt3(h) was added to a mixture containing 8mM MOPS pH 7.0, 0.2 mM EDTA, and 50 μM EAIYAAPFAKKK, in such amount thatthe resulting concentration of FLT3(h) was 28.3 nM. This mixture wasadded to the stock solution of the tested compound. The reaction wasinitiated by the addition of the MgATP mix in such amount that theresulting concentration of Mg acetate in the reaction mixture was 10 mMand [γ-³³P-ATP] (specific activity approx. 500 cpm/pmol) was 200 μM.After incubation for 40 minutes at room temperature, the reaction wasstopped by the addition of 3% phosphoric acid solution. 10 μL of thereaction was then spotted onto a P30 filtermat and washed three timesfor 5 minutes in 75 mM phosphoric acid and once in methanol prior todrying and scintillation counting.

TRKA Assay

TRKA(h) was diluted in the buffer (20 mM MOPS, 1 mM EDTA, 0.01% Brij-35,5% Glycerol, 0.1% β-mercaptoethanol, 1 mg/mL BSAs) to the concentrationof 1.01 mg/mL prior to addition to the reaction mix.

The above stock solution of TRKA(h) was added to a mixture containing 8mM MOPS pH 7.0, 0.2 mM EDTA, and 250 μM KKKSPGEYVNIEFG, in such amountthat the resulting concentration of TRKA(h) was 28.2 nM. This mixturewas added to the stock solution of the tested compound. The reaction wasinitiated by the addition of the MgATP mix in such amount that theresulting concentration of Mg acetate in the reaction mixture was 10 mMand [γ-³³P-ATP] (specific activity approx. 500 cpm/pmol) was 120 μM.After incubation for 40 minutes at room temperature, the reaction wasstopped by the addition of 3% phosphoric acid solution. 10 μL of thereaction was then spotted onto a P30 filtermat and washed three timesfor 5 minutes in 75 mM phosphoric acid and once in methanol prior todrying and scintillation counting.

RESULTS

compound CLK2 CLK4 FLT3 HIPK1 HIPK2 HIPK3 DYRK2 TRKA  6A B A B B C C  6DC B C C  7A A A B B B  7B A A A A A C  7C C C C  7D C C C B C  7F B B BA  8B B B C  8C C C C  8D C  8E C C C  9 A A A A B C 12B C B 17E C C 23B B C 54 C C B B 55 B B 61 A A B A C 62 C C B B 65 A B B 66 B B C 70 B BC 71 B C C 73 C C 74 B C 80 B 81 C C C A: IC₅₀ < 0.100 μM B: IC₅₀ < 1.00μM C: IC₅₀ < 5.00 μM

The invention claimed is:
 1. A compound represented by general formula(I):

or a pharmaceutically acceptable salt, solvate or a prodrug thereof,wherein: L² is selected from the group consisting of a bond, —O—; L⁶ isselected from the group consisting of a bond, —O—; L⁷ is selected fromthe group consisting of a bond, —N(R¹¹)—; -L⁵-R⁵ is heteroaryl,unsubstituted or substituted; R² is selected from the group consistingof H; —CF₃; —OH; —NH₂; —Cl; —Br; —F; C₁-C₆ alkyl; -L³-R³ is selectedfrom the group consisting of aryl; biaryl; heterocyclylaryl;heteroarylaryl; wherein each of the substituent moieties isunsubstituted or substituted; R⁶ is selected from the group consistingof H; —CF₃; —OH; —NH₂; —Cl; —Br; —F; C₁-C₆ alkyl; aryl; heteroaryl;wherein each of the substituent moieties is unsubstituted orsubstituted; R⁷ is selected from the group consisting of H; C₁-C₆ alkyl;aryl; cycloalkyl; heterocyclyl; heteroaryl; biaryl; heteroarylaryl;arylheteroaryl; heterocyclylaryl; heterocyclylheteroaryl; wherein eachof the substituent moieties is unsubstituted or substituted; R¹¹ isselected from the group consisting of H, C₁-C₆ alkyl; provided that thesubstituent in position 5 (L5-R5) is not oxadiazolyl ormethyl-oxadiazolyl; wherein: “alkyl” means an aliphatic hydrocarbongroup which may be straight or branched, whereas the alkyl isunsubstituted or substituted by one or more substituents which can bethe same or different, each substituent being independently selectedfrom the group consisting of F, Cl, Br, CF₃, OCF₃, OR⁹, SR⁹, SOH, SO₂H,SO₂N(H, C₁-C₄ alkyl)₂, CHO, COO(H, C₁-C₄ alkyl), COH, C(O)N(H, C₁-C₄alkyl), O(CH₂)_(p)N(CH₃)₂ and NR⁹R¹⁰; “aryl” means an aromaticmonocyclic or polycyclic ring system containing 6 to 14 carbon atoms,whereas the aryl is unsubstituted or substituted by one or moresubstituents which can be the same or different, each substituent beingindependently selected from the group consisting of F, Cl, Br, CF₃,OCF₃, OR⁹, [H.K.1]SO₂H, SO₂N(H, C₁-C₄ alkyl)₂, CHO, COO(H, C₁-C₄ alkyl),COH, C(O)N(H, C₁-C₄ alkyl), NR⁹R¹⁰, —(CR⁹R¹⁰)_(p)R^(9a),O(CH₂)_(p)N(CH₃)₂ and —(CR⁹R¹⁰)_(p)OR^(9a); “cycloalkyl” means analiphatic monocyclic or bicyclic ring system comprising 3 to 10 carbonatoms, whereas the cycloalkyl is unsubstituted or substituted by one ormore substituents which can be the same or different, each substituentbeing independently selected from the group consisting of F, Cl, Br,CF₃, OCF₃, OR⁹, SR⁹, SOH, SO₂H, SO₂N(H, C₁-C₄ alkyl)₂, CHO, COO(H, C₁-C₄alkyl), COH, C(O)N(H, C₁-C₄ alkyl), NR⁹R¹⁰, —(CR⁹R¹⁰)_(p)R^(9a),O(CH₂)_(p)N(CH₃)₂ and —(CR⁹R¹⁰)_(p)OR^(9a); “heterocyclyl” means analiphatic monocyclic or bicyclic ring system containing 3 to 10 carbonatoms, preferably 4 to 8 carbon atoms, and at least one heteroatomselected from the group consisting of nitrogen, oxygen and sulfur,whereas the heterocyclyl is unsubstituted or substituted by one or moresubstituents which can be the same or different, each substituent beingindependently selected from the group consisting of F, Cl, Br, CF₃,OCF₃, OR⁹, SR⁹, SOH, SO₂H, SO₂N(H, C₁-C₄ alkyl)₂, CHO, COO(H, C₁-C₄alkyl), COH, C(O)N(H, C₁-C₄ alkyl), NR⁹R¹⁰, —(CR⁹R¹⁰)_(p)R^(9a),O(CH₂)_(p)N(CH₃)₂ and —(CR⁹R¹⁰)_(p)OR^(9a); “heteroaryl” means anaromatic monocyclic or bicyclic ring system containing 1 to 14 carbonatoms, and at least one heteroatom selected from the group consisting ofnitrogen, oxygen and sulfur, whereas the heteroaryl is unsubstituted orsubstituted by one or more substituents which can be the same ordifferent, each substituent being independently selected from the groupconsisting of F, Cl, Br, CF₃, OCF₃, OR⁹, SR⁹, SOH, SO₂H, SO₂N(H, C₁-C₄alkyl)₂, CHO, COO(H, C₁-C₄ alkyl), COH, C(O)N(H, C₁-C₄ alkyl), NR⁹R¹⁰,—(CR⁹R¹⁰)_(p)R^(9a), O(CH₂)_(p)N(CH₃)₂ and —(CR⁹R¹⁰)_(p)OR^(9a);“biaryl” means an aryl-aryl- group in which each of the aryls isindependently as previously described; “bi(heteroaryl)” means anheteroaryl-heteroaryl- group in which each of the heteroaryls isindependently as previously described; “cycloalkylaryl” means acycloalkyl-aryl- group in which the cycloalkyl and aryl are aspreviously described; “heterocyclylaryl” means a heterocyclyl-aryl-group in which the heterocyclyl and aryl are as previously described;“heteroarylaryl” means a heteroaryl-aryl- group in which the heteroaryland aryl are as previously described; “arylheteroaryl” means anaryl-heteroaryl- group in which the aryl and heteroaryl are aspreviously described; “cycloalkylheteroaryl” means acycloalkyl-heteroaryl- group in which the heteroaryl and cycloalkyl areas previously described; “heterocyclylheteroaryl” means aheterocyclyl-heteroaryl- group in which the heterocyclyl and heteroarylare as previously described; wherein each of aryl, cycloalkyl,heterocyclyl, heteroaryl, biaryl, bi(heteroaryl), cycloalkylaryl,heterocyclylaryl, heteroarylaryl, arylheteroaryl, cycloalkylheteroaryl,and heterocyclylheteroaryl can be bound directly or via a methylene orethylene spacer; p is an integer in the range of from 1 to 7; R⁹ is H orC1-C6 alkyl, unsubstituted or optionally substituted by —OH, —NH₂,—N(CH₃)₂; R^(9a) is H or C1-C6 alkyl, unsubstituted or optionallysubstituted by —OH, —NH₂, —N(CH₃)₂; R¹⁰ is H or C1-C6 alkyl,unsubstituted or optionally substituted by —OH, —NH₂, —N(CH₃)₂.
 2. Thecompound of claim 1, wherein -L-R⁵ is substituted by at least onesubstituent selected from the group consisting of F, Cl, Br, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy,propoxy, isopropoxy, OH, NH₂, N(CH₃)₂, O(CH₂)_(p)N(CH₃)₂.
 3. Thecompound of any one of the preceding claims, wherein -L³-R³ issubstituted by at least one substituent selected from the groupconsisting of F, Cl, Br, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, OH, NH₂,N(CH₃)₂, O(CH₂)_(p)N(CH₃)₂.
 4. The compound of claim 1, wherein theheteroaryl moiety is selected from a 5-membered or 6-membered ring, or afused bicyclic system consisting of two 5-membered rings, two 6-memberedrings or one 5-membered and one 6-membered ring, and wherein theheteroaryl moiety comprises at least one nitrogen atom and isunsubstituted or substituted.
 5. The compound of claim 1, wherein thearyl moiety is selected from phenyl, naphthyl; biaryl moiety isbiphenyl; heteroaryl moiety is pyrazolyl; wherein each moiety isunsubstituted or substituted.
 6. The compound of claim 1, wherein-L²-R², -L⁶-R⁶, -L⁷-R⁷ are hydrogens.
 7. The compound of claim 1,wherein -L³-R³ is aryl or biaryl, unsubstituted or substituted, and-L⁵-R⁵ is heteroaryl, unsubstituted or substituted.
 8. A pharmaceuticalcomposition comprising at least one compound of formula (I) according toclaim 1 and at least one pharmaceutically acceptable auxiliary compound.